Mitochondria in Health and Disease 1848193327, 9781848193321, 0857012886, 9780857012883

Table of contents :
Mitochondria in Health and Disease by Ray Griffiths
Contents
Foreword by Lorraine Nicolle
Disclaimer
Abbreviations
Part I. Mitochondrial Functions: The Doorway to Understanding the Body as a Whole
1. What Are Mitochondria?
2. Enabling Evolution
3. Energy Production
4. Mitochondrial Dynamics
5. Maintaining Allostasis
6. Acetyl-CoA: A Vital Energy Source and Controller of a Cell
7. Synthesizing Cellular Components
8. Ketone Metabolism
9. Altering Immune Function
10. Creating Short Bursts of Rapid Energy
11. Calcium Storage and Regulation
12. Apoptosis: Programmed Cell Death
13. Haeme Production
14. Supporting Kidney Detoxification and Hormone Synthesis
15. Health, Toxicity and Hormesis
Part II. The Influence of Mitochondria in Disease
16. Diets to Support Mitochondrial Function
17. Laboratory Tests and Biomarkers Related to Mitochondrial Function
18. Insulin Resistance and Type 2 Diabetes
19. Hypertension
20. Heart Disease
21. Cholesterol Metabolism
22. Autoimmune Disease: The Emerging Field of Immunometabolism
23. Fatigue
24. Neurodegeneration
25. Cancer
26. Osteoarthritis
27. Osteoporosis
28. Chronic Pain
29. Depression
30. Autism Spectrum Disorders
Final Word
Appendix 1: Table of Fat Types
Appendix 2: Nutrient Dosage Ranges from Research Studies
Glossary
References
Subject Index
Author Index

Citation preview

‘The scope and detail of conditions covered within this book, combined with functional testing and appropriate interventions, offers a really useful handbook and tool to complement the practitioner in clinic.’ – Nina Bailey BSc (Hons), MSc, PhD (Cantab), RNutr Head of Nutrition at Igennus Healthcare Nutrition ‘A thoughtful and thorough explanation of mitochondrial function and the role it plays in generating disease.’ – Leyla El Moudden, DipHerb, DipNat, mANP, General Secretary of Association of Naturopathic Practitioners

This innovative book explores the incredibly complex biochemical roles of mitochondria in health and disease. When healthy, mitochondria provide us with 90 per cent of our body’s energy. When unhealthy, this can lead to many chronic and degenerative conditions, including cancer and Alzheimer’s disease. This guide helps practitioners to identify the mitochondrial dysfunction underlying a wide range of health complaints, and provides inspiration about relevant and emerging mitochondria-supportive dietary regimes and nutrients to explore within the model of personalized nutrition.

Ray Griffiths MSc, MBANT, Registered Nutritionist and lecturer. Ray lectures on a diverse range of subjects such as Parkinson’s disease, cancer, ageing and mitochondria.

Lorraine Nicolle MSc is a Registered Nutritionist (MBANT) and an educator and author in personalized nutrition. www. lorrainenicollenutrition.co.uk

Mitochondria in Health and Disease

Ray Griffiths

Edited by Lorraine Nicolle, this series of accessible, evidence-based, practical guides is essential reading for practitioners and students of clinical nutrition, and all other primary and complementary healthcare professionals interested in an approach that responds to the unique health needs of every individual. Each book in the series is a powerful new tool to help practitioners achieve significant clinical improvements for their clients/patients through the cutting-edge paradigms of personalized nutrition and lifestyle medicine. 

Mitochondria in Health and Disease

What are the functions of mitochondria in the human body? Why might they stop working properly and what can happen as a result? How can personalized nutrition help to optimize mitochondrial function and prevent or address chronic conditions?

Ray Griffiths

www.singingdragon.com

Cover design: Adam Renvoize

Personalized Nutrition and Lifestyle Medicine for Healthcare Practitioners Series Editor Lorraine Nicolle

Mitochondria in Health and Disease

Personalized Nutrition and Lifestyle Medicine for Healthcare Practitioners Edited by Lorraine Nicolle, this series of accessible, evidence-based, practical guides is essential reading for practitioners and students of clinical nutrition, and all other primary and complementary healthcare professionals interested in an approach that responds to the unique health needs of every individual. Each book in the series is a powerful new tool to help practitioners achieve significant clinical improvements for their clients/patients through the cutting-edge paradigm of personalized nutrition and lifestyle medicine. Lorraine Nicolle MSc is a Registered Nutritionist (MBANT) and an educator and author in personalized nutrition. www.lorrainenicollenutrition.co.uk

of related interest Biochemical Imbalances in Disease A Practitioner’s Handbook Edited by Lorraine Nicolle and Ann Woodriff Beirne ISBN 978 1 84819 033 7 eISBN 978 0 85701 028 5

The Functional Nutrition Cookbook Addressing Biochemical Imbalances through Diet Lorraine Nicolle and Christine Bailey Foreword by Laurie Hofmann ISBN 978 1 84819 079 5 eISBN 978 0 85701 052 0

Mitochondria in Health and Disease Part of Personalized Nutrition and Lifestyle Medicine for Healthcare Practitioners series

Ray Griffiths Foreword by Lorraine Nicolle

Excerpt on page 29 reprinted from Lynn Margulis copyright © 2012 by Dorian Sagan, used with permission from Chelsea Green Publishing (www.chelseagreen.com). First published in 2018 by Singing Dragon an imprint of Jessica Kingsley Publishers 73 Collier Street London N1 9BE, UK and 400 Market Street, Suite 400 Philadelphia, PA 19106, USA www.singingdragon.com Copyright © Ray Griffiths 2018 Foreword copyright © Lorraine Nicolle 2018 Front cover image source: Shutterstock®. The cover image is for illustrative purposes only, and any person featuring is a model. All rights reserved. No part of this publication may be reproduced in any material form (including photocopying, storing in any medium by electronic means or transmitting) without the written permission of the copyright owner except in accordance with the provisions of the law or under terms of a licence issued in the UK by the Copyright Licensing Agency Ltd. www.cla.co.uk or in overseas territories by the relevant reproduction rights organization, for details see www.ifrro.org. Applications for the copyright owner’s written permission to reproduce any part of this publication should be addressed to the publisher. Warning: The doing of an unauthorized act in relation to a copyright work may result in both a civil claim for damages and criminal prosecution. Library of Congress Cataloging in Publication Data Names: Griffiths, Ray (Nutritional therapist), author. Title: Mitochondria in health and disease : personalized nutrition for healthcare practitioners / Ray Griffiths. Description: London ; Philadelphia : Jessica Kingsley Publishers, 2018. | Includes bibliographical references and index. Identifiers: LCCN 2017041141 (print) | LCCN 2017040015 (ebook) | ISBN 9780857012883 (ebook) | ISBN 9781848193321 (alk. paper) Subjects: | MESH: Mitochondrial Diseases--diet therapy | Mitochondria--physiology | Mitochondria--metabolism | Adenosine Triphosphate--physiology | Mitochondria--pathology Classification: LCC QH603.M5 (print) | LCC QH603.M5 (ebook) | NLM WD 200.5.M6 | DDC 571.6/57--dc23 LC record available at https://lccn.loc.gov/2017040015 British Library Cataloguing in Publication Data A CIP catalogue record for this book is available from the British Library ISBN 978 1 84819 332 1 eISBN 978 0 85701 288 3

Contents

Foreword by Lorraine Nicolle

7

Disclaimer

10

Abbreviations

11

Part I

Mitochondrial Functions: The Doorway to Understanding the Body as a Whole

13

1

What Are Mitochondria?

16

2

Enabling Evolution 

22

3

Energy Production

30

4

Mitochondrial Dynamics

44

5

Maintaining Allostasis

62

6

Acetyl-CoA: A Vital Energy Source and Controller of a Cell

67

7

Synthesizing Cellular Components

73

8

Ketone Metabolism

80

9

Altering Immune Function

86

10

Creating Short Bursts of Rapid Energy

98

11

Calcium Storage and Regulation

12

Apoptosis: Programmed Cell Death

111

13

Haeme Production

114

100

14

Supporting Kidney Detoxification and Hormone Synthesis

118

15

Health, Toxicity and Hormesis

121

Part II

The Influence of Mitochondria in Disease

129

16

Diets to Support Mitochondrial Function

131

17

Laboratory Tests and Biomarkers Related to Mitochondrial Function

148

18

Insulin Resistance and Type 2 Diabetes

159

19

Hypertension

169

20

Heart Disease

177

21

Cholesterol Metabolism

185

22

Autoimmune Disease: The Emerging Field of Immunometabolism

194

23

Fatigue

202

24

Neurodegeneration

25

Cancer

222

26

Osteoarthritis

237

27

Osteoporosis

241

28

Chronic Pain

246

29

Depression

251

30

Autism Spectrum Disorders

259

211

Final Word

265

Appendix 1: Table of Fat Types

267

Appendix 2: Nutrient Dosage Ranges from Research Studies

268

Glossary

274

References

279

Subject Index

312

Author Index

328

Foreword

Welcome to the first of a new series of books on Personalized Nutrition and Lifestyle Medicine. Written and edited by healthcare practitioners, for practitioners, this series aims to help facilitate new levels of success with individuals striving for optimal health and peak performance. We’re all well aware that chronic illness is far too prevalent and its consequences too severe – for patients, their families and communities, for over-burdened healthcare systems and even for nations’ financial resources and GDP. Our seeming inability to slow the march of chronic disease may even be threatening the health of future generations. But there is hope on the horizon, with the growing recognition that ageing populations could be far more healthy, happy and active if we were brave enough to start redirecting resources away from drug‑based interventions that aim to suppress symptoms, towards more personalized, lifestyle-based healthcare approaches. Such ‘systems biology’ approaches include Functional Medicine, Ecological Medicine and Clinical Psychoneuroimmunology, to name but a few. They strive to identify and tackle the underlying causes of an individual’s ill-health. They focus on providing bespoke interventions, tailored to the unique set of biochemical needs of the patient, and which are based first and foremost on nutrition and lifestyle changes.1 1

Such an approach does not reject the use of pharmaceuticals but considers their use should be a last resort, rather than an initial intervention. This is different to situations of acute care, where drugs and/or surgery may be more appropriate as a first option.

7

M I TO C H O N D R I A I N H E A LT H A N D D I S E A S E

Nutrition and lifestyle are our most powerful tools because they are ‘epigenetic’ inputs – they alter the behaviour of our genes, which in turn sets us on particular trajectories of health and disease. This first book of the series focuses on the role of the powerhouses of our cells – the mitochondria – and how their functioning affects not only our ability to produce energy, but a great many other aspects of our health. Many of today’s most common diseases, including diabetes, cardiovascular disease, cancer and dementia, are driven in part by mitochondrial function going awry. So for anyone striving for optimal health, it makes sense to assess mitochondrial function and provide targeted support where necessary. The author Ray Griffiths is passionate about the workings of these tiny organelles. He has scoured more than 1500 scientific papers to compile this repository of information on the various tasks that mitochondria do for us, why and how they can go wrong, what happens when they do, and what practitioners can do to identify such dysfunction and intervene in a way that improves health and longevity. You might notice some recurring themes throughout this text and the books that follow. Such themes represent real progression in healthcare thinking. They include: • That the supreme governor of our health is not what genes we have inherited, but the behaviour of those genes. In turn, this is altered by lifestyle, especially by what we eat, how much we eat and the timing of our food intake. • That this misbehaviour of our genes disrupts the function of various body systems; and that most degenerative disease is preceded by years of such systems malfunction. • That all body systems are connected, such that dysfunction in one biological process can have far-reaching effects on other body systems. • That different biological systems may be impaired in different individuals with the same disease, and that consequently people with exactly the same symptoms may require very different interventions.

8

F ore word

• That some individuals may need certain nutrients at far higher levels than the standard recommended intakes, in order to achieve ‘normal’ functioning. Getting anything less may cause cells to accumulate damage insidiously throughout the years and eventually trigger chronic illness. • That far from comprising merely human cells, it turns out that we’re human-microbe hybrids. The activity of the microbes we carry impacts our health perhaps just as much as do our own cellular functions. And, guess what? Our microbial balance is significantly determined by what we eat. • That human health requires balance: between the various body system functions and between different environmental inputs. An example in this book is the power of hormesis: timely and appropriate stressors (like metabolic switching/ketogenesis and/or the use of ‘toxic’ phytochemicals) produce counteractive, health-promoting responses like detoxification, antioxidant activity and the renewal of cell and organelle populations. (Many pharmaceuticals create imbalance – otherwise known as ‘side‑effects’.) • That the evidence on which we rely should encompass far more than simply randomized controlled trials. Such studies are designed to minimize variation across groups of participants. In contrast, personalised approaches in healthcare require individual variation to be embraced (n = 1). Advances in nutrigenomics, informatics and wearable technologies will significantly strengthen this new evidence base. This book is for everyone who is excited by developments like these and is keen to explore how they can be applied to real-world situations in order to make things better: to reduce the risk of chronic illness, to improve outcomes for people living with seemingly entrenched diseases, to age better and to reach peak levels of physical and mental performance. Lorraine Nicolle MSc, MBANT, CNHC Series Editor www.LorraineNicolleNutrition.co.uk 9

Disclaimer

The information contained in this book is for the explicit use of appropriately trained healthcare practitioners. Only healthcare practitioners are qualified to integrate information from client histories and laboratory results. In this way, healthcare practitioners are able to produce nutritional guidance tailored to an individual’s unique biochemistry. Part II contains information relating to mitochondrial involvement in many complex health conditions. The author is in no way claiming that using this information for an intervention will resolve these conditions. The information is more a thought-provoking exercise, to enable a practitioner to explore other avenues when working with complex patients. In accordance with the act, Chapter 25, ‘Cancer’, is designed to help inform a healthcare practitioner about cancer prevention strategies and palliative care only as a complement to primary medical care.

10

Abbreviations

ABC

ATP-binding cassette

EGCG epigallocatechin-3-gallate

ACE angiotensin-converting enzyme

eNOS

endothelial nitric oxide synthase

ADP

adenosine diphosphate

EPA

eicosapentaenoic acid

AGE

advanced glycation endproducts

ER

endoplasmic reticulum

ETC

electron transport chain

AMP

adenosine monophosphate

FAD

flavin adenine dinucleotide

AMPK

AMP-activated protein kinase

ARE

antioxidant response element

FODMAP fermentable oligo-, di- and monosaccharides, and polyols GI

glycaemic index

ATP

adenosine triphosphate

HDL

high-density lipoprotein

BMI

body mass index

HDL-C

HDL cholesterol

CFS

chronic fatigue syndrome

HIF

hypoxia inducible factor

CIC

citrate carrier

HOMA

CJD

Creutzfeldt-Jakob disease (‘mad cow disease’)

homeostasis model assessment

IMM

CLA

conjugated linoleic acid

inner mitochondrial membrane

CNS

central nervous system

iNOS

CoA

coenzyme A

inducible nitric oxide synthase

CoQ10

coenzyme Q10

KATP

DAMP damage-associated molecular pattern

ATP-sensitive potassium channels

LCFA

long-chain fatty acid

DHA

docosahexaenoic acid

LDL

low-density lipoprotein

DII

dietary inflammatory index

LDL-C

LDL cholesterol

DNA

deoxyribonucleic acid

LPS lipopolysaccharide

11

M I TO C H O N D R I A I N H E A LT H A N D D I S E A S E

MAM mitochondria-associated ER membrane

PET

positron emission tomography

MAVS

mitochondrial antiviralsignalling protein

PGC1-α

the master co-ordinator of mitochondrial biogenesis

MCT

medium-chain triglyceride

PLA2

phospholipase A2

MND

motor neurone disease

PPAR

MPC

mitochondrial pyruvate carrier

peroxisome proliferatoractivated receptor

PUFA

polyunsaturated fatty acid

mPTP

mitochondrial permeability transition pore

RAGE

receptor for advanced glycation end-products

mtDNA

mitochondrial DNA

RNI

reference nutrition intake

MS

multiple sclerosis

RNS

reactive nitrogen species

MUFA

monounsaturated fatty acid

ROS

reactive oxygen species

NAD+

SCFA

short-chain fatty acid

nicotinamide adenine dinucleotide (oxidized)

SERM

selective oestrogen receptor modifier

NADH

nicotinamide adenine dinucleotide (reduced)

SFA

saturated fatty acid

NADPH

nicotinamide adenine dinucleotide phosphate (reduced)

SMT

somatic mutation theory

SOD

superoxide dismutase

SREBP

sterol receptor elementbinding protein

SSRI

selective serotonin reuptake inhibitor

TCA

tricarboxylic acid

TFAM

transcription factor of activated mitochondria

NET

neutrophil extracellular trap

NGF

nerve growth factor

NLR

neutrophil to lymphocyte ratio

NMDA N-methyl-D-aspartate NOX

NADPH oxidase

Tg thyroglobulin

Nrf

nuclear respiratory factor

TG tyglyglycine

NSAID

non-steroidal antiinflammatory drug

TLR

toll-like receptor

TNT

tunnelling nanotube

outer mitochondrial membrane

TPO thyroperoxidase

OMM

TRAF6

tumour necrosis factor receptor-associated factor 6

UPRmt

mitochondrial unfolded protein response

PAMP pathogen-associated molecular pattern

VEGF

vascular endothelial growth factor

PDC

VLDL

very low density lipoprotein

OPC oligomeric proanthocyanidins OXPHOS oxidative phosphorylation

12

pyruvate dehydrogenase complex

Part I Mitochondrial Functions The Doorway to Understanding the Body as a Whole

Understanding how mitochondria function in our cells gives us vital clues about maintaining our long-term health and how to help protect ourselves from illness and disease. In fact many chronic diseases are due to a lack of active mitochondrial regeneration rather than general ageing per se. It’s the gradual acceptance of the proactive rather than passive role that mitochondria play in health that has allowed this greater understanding of its regenerative powers. In the past ten years there has been an exponential increase in our knowledge of the highly complex internal and external workings of mitochondria. What we are discovering is a remarkable level of innate intelligence that has taken everyone by surprise. Unexpectedly, it’s the fine tuning of genes by mitochondria and the cell, spanning over millions of years, that has allowed us, and all intelligent life, to evolve. Chapter 2, ‘Enabling Evolution’, examines this idea in more detail. Tapping into the secrets of mitochondrial regeneration can improve the efficiency and health of the whole body. Exercise is a great way to regenerate our mitochondria. It may not be obvious, but athletes in training are generating and regenerating their mitochondria to help them achieve their peak performance. Chapter 4, ‘Mitochondrial Dynamics’, explores the regenerative powers of mitochondria. 13

M I TO C H O N D R I A I N H E A LT H A N D D I S E A S E

The choice between the life and death of a cell often lies in the hands of mitochondria. Fats, cholesterol and nucleotides, for cell growth and proliferation, rely on components generated within mitochondria. Conversely, cell fate decisions rely on mitochondria to sound the death knell for worn-out cells. In cancer there tends to be too much growth, and in neurodegeneration, too much cell death – mitochondria are heavily implicated in both. Chapter 7, ‘Synthesizing Cellular Components’, explores inflammation, proliferation and cancer, and Chapter 12 on apoptosis explores programmed cell death. The continuum between insulin resistance, metabolic syndrome, obesity and type 2 diabetes is a worldwide problem. Our lack of knowledge regarding mitochondria’s all-important role in how our cells regulate energy and growth is starkly apparent. The old adage of a calorie being a calorie is completely wrong. It really does depend on whether mitochondria are switched to ‘burn mode’ or ‘build mode’ and in what dietary form the calories are arriving. Immerse yourself in Chapter 7, ‘Synthesizing Cellular Components’, to find out more. Calories are not passive but highly active participants, which mould and shape their journey through the body. Calories converted to acetyl‑CoA have subtle effects within the cell, beyond energy production. AcetylCoA can switch genes in DNA and can alter protein behaviour. Therefore calories converted to acetyl-CoA are highly proactive and interactive with all their mitochondrial, cellular and nuclear hosts. Chapter 6, ‘Acetyl‑CoA’, delves into the subtlety of this ubiquitous compound. Mitochondria have to be metabolically flexible. That is, they need to be able to change their behaviour to burn carbohydrate or fat in response to the food we eat. To enable this essential metabolic flexibility, a process called the Randle cycle determines the correct mode of operation in mitochondria for the type of food presented to the cell. Diabetes type 1 and 2 are examples of where mitochondria become metabolically inflexible. Without insulin to help direct mitochondria, inappropriate mitochondrial responses to dietary protein, fat and carbohydrate can occur. A patient may have ample blood glucose, yet insufficient insulin to allow a cell or mitochondrion to metabolize the glucose. See Chapter 5, ‘Maintaining Allostasis’, for more details. The immune system is very sensitive to the activities of mitochondria. There are very different energy requirements and resources needed 14

M itochondrial F unction

by immune cells, depending on their activity. Quiescent T cells on surveillance duties have very different needs from the highly active effector T cells, battling at the front line of an immune response. What is absolutely fascinating is that we can use diet to alter the behaviour of mitochondria and the immune system. One example of how this has been put to great use for many years is in the treatment of multiple sclerosis. The impact of the Western diet on autoimmunity, inflammation and cancer now becomes far more obvious when viewed through its effect on mitochondria and the immune system. We are used to using medicine and nutrition to modify immune system behaviour from the outside of immune cells. However, moving away from the damaging effects of the Western diet allows mitochondria to change their behaviour from inside immune cells. This in turn catalyses the immune system to be less inflammatory and proliferative. Read Chapter 9, ‘Altering Immune Function’, to find out more. Calcium and iron are vital minerals for our body and metabolism. What is not often considered is their damaging dark side, with mitochondria being particularly vulnerable to the damaging effects of these mineral ions. It’s difficult to understand why the dark side of these two mineral ions is under-reported, but it is absolutely essential to take heed of their negative effects, to avoid causing potential harm. Calcium and iron are discussed in Chapter 11, ‘Calcium Storage and Regulation’, and Chapter 13, ‘Haeme Production’. All too often, modern medicine attempts to understand health and disease by isolating body systems, and then subsequently missing vital clues about the whole patient. This book is looking to address this oversight by examining the complexities of mitochondria, our metabolism and the body – both in individual detail and as a whole. This requires a painstaking journey of discovery and an exploration of every aspect of mitochondrial function – there are no short cuts! Journey with me in examining the awe-inspiring innate intelligence of our mitochondria and I guarantee that you will not be disappointed! But one thing is certain: to understand the whole you must look at the whole. Henrik Kacser, quoted in Kell (2009)

15

1 What Are Mitochondria?

The name mitochondrion is derived from the Greek ‘mitos’ (thread) and ‘chondros’ (granule). It was coined by microbiologist Carl Benda in 1898. Mitochondria are organelles (specialized subunits within a cell) whose main function is to produce the energy the cell needs to function, and regulate cellular metabolism. Outer mitochondrial membrane (OMM)

Inner mitochondrial membrane (IMM)

The mitochondrial matrix

Intermembrane space

Figure 1.1 The four main components of a mitochondrion

Incredibly, there are around a thousand proteins required to maintain the function of a mitochondrion. Thirteen of these proteins are encoded by mitochondrial DNA (mtDNA) and the remainder by nuclear DNA (Zhang et al. 2012).

Through evolution, many mitochondrial genes have been transferred to nuclear DNA, and, in the process, have efficiently edited out many unnecessary genes. Mitochondria allow several thousand times more 16

What A re M itochondria?

power per gene compared to our bacterial ancestors (Lane & Martin 2010). This is a stunning quantum leap in gene power compared to bacteria. It ensures that animals, plants and fungi are highly adaptable and highly evolvable within their environment. Put simply, without this large gain in gene power, it is unlikely that humans would ever have evolved away from primitive early life-forms. A mitochondrion generates 150–200 millivolts across its 5-nanometre membrane. These figures don’t sound that impressive until they are translated to a size that people can relate to. If the field strength were measured per metre, a mitochondrion would be producing a whopping 30 million volts. Lane and Martin (2010) have estimated that, size for size, a mitochondrion produces as much energy as a bolt of lightning! The inheritance of mtDNA is passed down by a mother to her child via the maternal line. A mother can therefore pass mtDNA mutations onto her children, but only her daughters will continue transmission of a mutation (Perier & Vila 2012). Mitochondria are often portrayed as a single mitochondrion in textbooks, but this image betrays the dynamic, motile, shape‑shifting qualities of this multi-functional organelle. Mitochondria have to be flexible enough to be able to constantly adapt to a cell’s ever‑changing energetic needs. Mitochondria fuse together and split apart in continual cycles of fusion and fission. Worn-out mitochondrial components are digested in a process called mitophagy. Mitophagy acts like a mitochondrial quality-control process that keeps efficient energy producers and meticulously ejects the lacklustre performers. Brand‑new mitochondria are created by mitochondrial biogenesis. It may come as a surprise to know that mitochondria are driven along cytoskeletal tracks inside cells by protein motors. These tracks are vital, particularly for neuronal function. The tracks are like rails that enable mitochondria to reach far along an axon and into the synapse. There are approximately 10 million billion mitochondria in an adult human. That is estimated to be roughly 10 per cent of total body weight. Mitochondria constitute 40 per cent of the cytosolic weight of many cells (Nisoli & Carruba 2006). The heart and the brain are the two organs with the highest energy demands of the human body. Every day brain and heart mitochondria have to synthesize around 6kg of ATP (adenosine triphosphate). 17

M I TO C H O N D R I A I N H E A LT H A N D D I S E A S E

This substantial amount of ATP is required to maintain normal brain function and to keep the heart pumping vital blood and nutrients throughout the body (Murray 2011; Zhu et al. 2012).

Adenosine triphosphate (ATP): ATP transports chemical energy within cells. It can be thought of as the ‘molecular unit of currency’ within cells.

Mitochondria are considered to be the main source of cellular reactive oxygen species (ROS). ROS are types of free radicals which in excess can damage cells, cell components and even mitochondria themselves. Once damaged by ROS, mitochondria are able to trigger the death of a whole cell through a process called apoptosis (programmed cell death). Surprisingly, though, some presence of ROS can be beneficial: a low level can trigger the genetic expression of antioxidant enzyme synthesis, which protect mitochondria from damage. This protective response is called hormesis (Calabrese et al. 2012). For further information about hormesis, please see Chapter 15, ‘Health, Toxicity and Hormesis’.

Reactive oxygen species (ROS): ROS are types of free radicals which in excess can damage cells, cell components and even mitochondria themselves. Surprisingly, low levels of ROS can lead to the gene expression of antioxidant enzymes which protect mitochondria from damage.

Dysfunctional mitochondria can play a major role in Parkinson’s disease, Alzheimer’s disease, Huntingdon’s disease, metabolic syndrome and many cancers (de Moura et al. 2010; Mabalirajan & Ghosh 2013). Although people tend to think that a high calorie intake will give them more energy, the exact opposite is true as an excessive macro‑nutrient intake (or over-nutrition) can eventually lead to decreased ATP synthesis in mitochondria (Mabalirajan & Ghosh 2013).

18

What A re M itochondria?

Macro-nutrients: proteins, carbs and fats (as opposed to micronutrients, which are vitamins and minerals). Over-nutrition: a form of malnutrition which can result from overconsumption of either macro- or micro-nutrients.

Overview of mitochondrial functions Each chapter in Part I covers a specific function of mitochondria, apart from the final chapter, which looks at the role of toxicity in relation to mitochondrial function. Chapter 2: Enabling Evolution. Mitochondria were once separate bacterial organisms in their own right. Initially cellular invaders or parasites, they have co-evolved with host organisms to now make the diversity of all animal and plant life possible. Chapter 3: Energy Production. Mitochondria are most well known for their role in energy production, synthesizing ATP from carbohydrate, fat and protein. Chapter 4: Mitochondrial Dynamics. The insatiable demand for energy within a cell requires mitochondria to be maintained at peak efficiency. Mitochondria also need to be highly mobile to be able to deliver energy to areas of high energetic need. This chapter examines how mitochondria work incessantly to sustain their efficiency and mobility. Chapter 5: Maintaining Allostasis. When presented with fats or carbohydrates, mitochondria have to be flexible enough to alter their behaviour to suit an incoming fuel source. Chapter 6: Acetyl-CoA. Both carbohydrate and fat provide mitochondria with acetyl-CoA to act as a fuel source and a marker for energy levels in a cell. In addition, acetyl-CoA can bind to protein and DNA, significantly altering the behaviour of both of them. This gives

19

M I TO C H O N D R I A I N H E A LT H A N D D I S E A S E

acetyl-CoA a dual role. First, as an energy source for mitochondria and second, as a major regulator of cell and mitochondrial behaviour. By binding to mitochondrial proteins, acetyl-CoA can effectively switch off mitochondria and protect them from an energy overload. Chapter 7: Synthesizing Cellular Components. Mitochondria are often  seen purely as energy producers for a cell. It’s a little-known fact that a cell depends on mitochondria for the fats, cholesterol and proteins required to build and repair cells. When producing energy, mitochondria are in a catabolic (breaking down molecules into smaller  units) mode. When engaged in the biosynthesis of cellular components, mitochondria are in an anabolic (constructing molecules from smaller units) mode. Chapter 8: Ketone Metabolism. The inability of the liver to metabolize high levels of fat leads to the formation of ketones in hepatic mitochondria. Ketones can both power and heal mitochondria in other tissues. Ketogenic diets (high-fat, low-carb diets that result in the production of a high amount of ketones) can be of benefit to people with certain health conditions and mitochondrial disorders. Chapter 9: Altering Immune Function. The actions of mitochondria within immune cells can alter immune cell behaviour. Dietary changes that impact mitochondria will also alter immune system activity – this is known as ‘immunometabolisation’. The generation of reactive oxygen species by mitochondria plays an important role in the effectiveness of the innate immune system, when immune cells need to engulf and kill microorganisms. Chapter 10: Creating Short Bursts of Rapid Energy. Fast-metabolizing tissues (such as muscle, the heart and the brain) need a readily available pool of energy at their disposal. Mitochondria work with the compound creatine to produce phosphocreatine for short bursts of rapid energy.

20

What A re M itochondria?

Chapter 11: Calcium Storage and Regulation. Cellular calcium levels have to be maintained within set limits to maintain the integrity of the cell. Mitochondria and the endoplasmic reticulum are the two organelles that act as calcium stores and regulators. Chapter 12: Apoptosis. Mitochondria control apoptosis, a type of programmed cell death. Leakage of cytochrome c from mitochondria is a primary step in the initiation of apoptosis. In neurodegenerative conditions there is excess apoptosis. In cancer, there is insufficient apoptosis. Chapter 13: Haeme Production. Synthesis of the iron-containing compound haeme starts and ends in mitochondria. Haeme is required for more than just haemoglobin. Haeme-containing cytochrome enzymes operate in the liver, nervous system, endocrine system and brain. Chapter 14: Supporting Kidney Detoxification and Hormone Synthesis. Mitochondria assist in the clearance of ammonia from the body by supporting several steps of the urea cycle. Steroid hormone synthesis is initiated in mitochondria with the production of pregnenolone, the ‘mother’ of all steroid hormones. Pregnenoloneproducing mitochondria can be found wherever steroid hormone synthesis is required: the adrenal glands, testis, ovaries, liver, skin and central nervous system. Chapter 15: Health, Toxicity and Hormesis. Strangely, mitochondria (and the whole body) improve their function and efficiency when faced with a small amount of toxicity. In part, we may reap the benefits of exercise through the toxicity of the free radicals generated during a work-out.

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2 Enabling Evolution

In this chapter we are going to follow the path that life on earth took which enabled all complex life-forms to exist – including plants, fungi and animals. Without exception, all complex life-forms needed mitochondria to evolve. When we think of mitochondria and energy production it is usually in the context of current health conditions. The secret history of these marvellous organelles that make our very existence possible is less known. Embedded within every single mitochondrion is the story of our own evolution; a story that is billions of years old, and which is every bit as enthralling as a captivating Brothers Grimm tale! Evolution is not an irrelevant event that occurred billions of years ago, back in the mists of time. All key prehistoric biochemical inventions, such as the tricarboxylic acid (TCA) cycle (see Chapter 3, ‘Energy Production’), electron transport chain (ETC; see Chapter 3) and adenosine triphosphate (ATP; see Chapter 3), are as alive and well in us now as they were then. As humans, we tend to forget this incredible biochemical and mitochondrial inheritance, which has enabled our very existence.

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Animals, plants and fungi are all highly complex life-forms whose evolution has been enabled by the mighty mitochondria. Our and their story began 3.5 to 4 billion years ago when the first organisms started to appear on Earth. These emerging primitive life-forms eventually divided into the three fundamental domains of life – Archaea, Bacteria (also known as Eubacteria) and Eukarya (a domain containing the more complex eukaryotic organisms).

THE THREE DOMAINS OF LIFE Archaea: single-celled organisms, which have no nucleus or any other organelles inside their cell. The most ancient organisms that have been discovered. Many archaea live in extreme environments and can withstand and thrive in much higher temperatures than bacteria. Bacteria: organisms that are usually single-celled, but with different cell characteristics to archaea. Eukarya: multi-cellular organisms, whose cells contain a nucleus and organelles.

Domains of life ‘Domains of life’ sounds a rather grandiose term, but this grandiosity can be justified when the awe-inspiring intelligence of all life is fully acknowledged. We should be eternally grateful that these early microscopic pioneers of biology have conserved so many of their attributes for our mutual benefit.

Prokaryotes: organisms whose cells have no organelles and a nucleus. Eukaryotes: organisms whose cells contain organelles and a nucleus.

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Until the latter part of the 20th century, there were assumed to be just two domains of life – Bacteria (comprising prokaryotes) and Eukarya (comprising eukaryotes). Prokaryotes can be defined as organisms without organelles and a nucleus. Conversely, the more evolved eukaryotes are defined as organisms with organelles and a nucleus. In 1990 Carl Woese and his team (Woese et al. 1990) identified that prokaryotes were, in fact, contained within two distinct domains – Bacteria and Archaea. Initially thought to be a type of bacteria, Archaea were duly promoted to their own unique domain. The name Archaea is derived from the Greek meaning ‘ancient ones’, which helps to encapsulate their connection to the early dawning of life on Earth. Domains

Bacteria

Kingdoms

Archaea

Plantae

Eukarya

Animalia

Fungi

Figure 2.1 How organisms are classified

Organisms within the Bacteria and Archaea domains are prokaryotic (without a nucleus or organelles). Organisms within the Eukarya domain are eukaryotic (with a nucleus and organelles). All the complex kingdoms of Plantae, Animalia and Fungi are within the Eukarya domain.

Endosymbiosis – the union of two domains to create a third domain Eukarya (comprising eukaryotes), the third domain of life, evolved much later than the other two domains, around 2 billion years ago. Eukaryotes were the result of the fusion of an archaea and an α-proteobacteria that it engulfed, in a process called endosymbiosis. The engulfed α-proteobacteria were a type of aerobic bacteria which enabled the archaea host to thrive in an oxygen-rich environment. This endosymbiosis conveyed qualities to eukaryotes which have enabled all complex multi-celled life to evolve and thrive. If anything in biology could be described as magical, then endosymbiosis gets

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very close. The quantum leap in evolution that endosymbiosis initiated was, and is, nothing short of awe-inspiring. All the plants and animal species that we take for granted in today’s world are here only by dint of this near-magical event.

The evolution of mitochondria The engulfed bacteria, or endosymbiont, further evolved to become mitochondria, the powerhouse of eukaryotic organisms. Eukaryotes differ from archaea and bacteria by having a nucleus and organelles, yet have been found to contain genetic material from both of these domains, affirming their unique ancestral heritage (Ku et al. 2015; Williams & Embley 2015). Eukaryotic cells are the cellular building blocks of Animalia, Plantae and Fungi kingdoms. Eukaryotes provide the biological components that enable all complex life, including ourselves, the ubiquitous Homo sapiens sapiens. α-Proteobacteria (prokaryotic cell)

Archaea host (prokaryotic cell)

Eukarya (mitochondria-containing eukaryotic cell) Figure 2.2 Endosymbiosis

Endosymbiosis occurred around 2 billion years ago when an archaea host cell united with an α-proteobacterium. This symbiotic union led to the evolution of a new domain of life called Eukarya. Mitochondria within eukaryotic cells evolved from α-proteobacteria. The creation of mitochondria provided a powerful boost to the evolution of eukaryotes, enabling them to evolve into higher life-forms.

The Plantae kingdom and the Great Oxidation Event Subsequent to the evolution of eukaryotes and mitochondria, the endosymbiosis of cyanobacteria (a group of photosynthesizing bacteria

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with a blue-green or cyan appearance) with another eukaryotic organism created the Plantae kingdom. Cyanobacteria as an endosymbiont evolved to become the chloroplasts of plants, allowing plants to photosynthesize oxygen from UV light (Dolan 2013). This new ability of plants to photosynthesize oxygen helped to catalyse a transformational change to the Earth’s atmosphere. Oxygen levels increased so significantly that many species became extinct. However, certain other species were able not only to survive this Great Oxidation Event, but to adapt and evolve. For these species, oxygen was no longer a toxic waste gas, but a vital life-giving component. Photosynthesis allowed electrons to be removed from water to produce oxygen. Conversely, the mitochondrial processes of aerobic respiration, or oxidative phosphorylation, reversed this process to add electrons back to produce water and the energy molecule ATP. In the Great Oxidation Event organisms with mitochondria were in a great position to take advantage of increased atmospheric and oceanic oxygen. Frustratingly, the benefits of oxygen also came at a high price because the damaging effects of a mitochondrion’s use of oxygen (resulting in the production of reactive oxygen species, causing oxidative stress) dramatically increased the likelihood of cell death (Hsia et al. 2013).

What was the evolutionary benefit of endosymbiosis? At first sight, the only major benefit of mitochondrial endosymbiosis (i.e. the symbiotic union of archaea hosts with an α-proteobacteria to create eukaryotic cells) would appear to be increased synthesis of energy, in the form of ATP (please refer to Chapter 3, ‘Energy Production’, for information on ATP and energy synthesis). Endosymbiosis allowed eukaryotic cells to increase their ATP output from their more efficient use of increasing global oxygen. Controversially, however, recent analysis suggests that this benefit may now not be as clear-cut as it seems. At first sight, it would appear that an increase in ATP (enabled by endosymbiosis) would be enough to convey an evolutionary advantage for eukaryotic cells (the building blocks of animals, plants and fungi). However, nothing is ever that straightforward in evolution!

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Confounding the increased energy theory, there are examples of prokaryotes (remember, these are bacteria and archaea) that can produce, size for size, just as much energy as eukaryotes – even without them having the benefit of mitochondria (Lane & Martin 2010). Furthermore, researchers have discovered mitochondria which do not even use oxygen (Ku et al. 2015). Other authors question why an endosymbiont (like a mitochondrion) would export all of its ATP production to its host, unlike any other organism, many of which would hold onto the energy for their own needs (van der Giezen 2011). Finally, why would a host tolerate the generation of reactive oxygen species from mitochondria (Dolan 2013)? The answer to what the benefit of mitochondrial endosymbiosis between host and endosymbiont may be is likely to be more subtle than at first realized. Yes, nearly all complex multi-celled life relies on the benefits conferred by mitochondria – and yes, the vast majority of eukaryotes have the ability to use aerobic respiration. However, these benefits are not sufficient to explain the evolution of complex animals, such as ourselves. One hypothesis that stands out as a possible answer is the idea that the genetic co-operation and gene transfer between mitochondrial DNA  and host DNA allowed for greater gene numbers and gene efficiency – and therefore more energy available per gene, compared to prokaryotes (Lane & Martin 2010). It is estimated that mitochondria containing eukaryotes can produce many thousand times more ATP compared to similar-sized prokaryotes. Relatively low ATP synthesis by prokaryotes (bacteria and archaea) constrains their evolution due to their inability to power the complex genetics required to step beyond their primitive structures. Through millions of years of evolution DNA accumulated many redundant genes, resulting in inefficient energy use by prokaryotic species. Endosymbiosis was an incredible opportunity for the host cell and mitochondrion to ‘clear out’ redundant genes and share or transfer others. This evolutionary efficiency drive may have resulted in eukaryotes having far more energy per gene than prokaryotes. With dramatically more energy per gene, eukaryotes were free to be far more inventive with their genes. The amazing complexity displayed by all animals, plants and fungi is likely to be down to increased gene 27

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power to more rapidly evolve to environmental challenge. Compared to eukaryotes, inefficient prokaryotes just didn’t (and still don’t) have the power per gene needed to evolve (Lane & Martin 2010). If this hypothesis holds true, it would have been impossible for a step-by-step, incremental evolution from prokaryote to eukaryote to occur. There just wouldn’t have been sufficient energy per gene for prokaryotes to evolve incrementally. Through endosymbiosis, mitochondria were the powerhouses and genetic engineers that drove the Cambrian explosion of new species over 500 million years ago. Mitochondria helped to pave the way for a vast array of life-forms to evolve and thrive. Through endosymbiosis it is highly likely that mitochondria have made our very existence possible!

Endosymbiosis – the 100-year journey from idea to acceptance Since Charles Darwin published the Origin of Species in 1859 there has been a general reluctance from academia to accept any evolutionary process other than step-by-step incremental changes in a species. The concept of endosymbiosis has its roots in the late 19th century, and many biologists expanded the theory throughout the early 20th century. One of the problems that the theory encountered was that it appeared to contradict Darwin’s idea of species competition through natural selection: endosymbiosis was, and is, a theory of co-operation, and therefore did not fit in with the prevailing paradigm (Blackstone 2016). For example, the host cell and mitochondrion had to co-operate genetically to enable the dramatic increase in power per gene found in eukaryotic cells. It took a no-nonsense approach in the late 20th century from biologist Lynn Margulis to rediscover and repackage the endosymbiosis theory until, along with others, it achieved general acceptance. The discovery that mitochondria had their own DNA provided solid evidence that they were once a separate entity (Sagan 1967). Margulis believed that evolution as competition was a distortion of Darwin’s work, and that networking and mutual dependence were much undervalued factors in the evolution of species (Margulis & Sagan 1986). 28

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I greatly admire Lynn Margulis’s sheer courage and stamina in sticking by the endosymbiosis theory, and carrying it through from being an unorthodoxy to an orthodoxy. I’m referring to the theory that the eukaryotic cell is a symbiotic union of primitive prokaryotic cells. This is one of the great achievements of twentieth-century evolutionary biology, and I greatly admire her for it. Richard Dawkins, evolutionary biologist (Sagan 2012)

In this chapter we have seen how mitochondria helped to support a crucial evolutionary stepping stone. This enabled life to make a quantum evolutionary leap from simplistic bacteria and archaea, to the magnificent splendour of animal, plant and fungal life-forms.

Key points for practitioners An appreciation of the evolutionary heritage of our cells and mitochondria can help practitioners develop more comprehensive philosophies and strategies to help support their patients. There is a school of thought that views a shift toward aerobic respiration as a form of devolution (or ‘de-evolving’) back to a more primitive state before mitochondria and oxidative phosphorylation existed (Setälä 1984). Rapid growth and wound healing are thought to tap into this primitive repair mechanism. Therefore, encouraging mitochondria to become aerobic once more could be seen as a retracing of evolutionary steps. When viewed from an evolutionary perspective, chronic inflammatory health conditions and cancer could be seen in a slightly different way: for example, wounds failing to heal may be caused by a reversion to primitive, protective cellular behaviours (Israel 1996). The realization that mitochondria were once bacteria helps us be more aware of how some classes of antibiotic could undermine energy production. Quinolones, aminoglycosides and β-lactams are all bactericidal antibiotics with a relationship to mitochondrial dysfunction (Kalghatgi et al. 2013).

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3 Energy Production

In this chapter we’re going to review the process of mitochondrial energy production from macronutrients, glucose, amino acids and fatty acids.

Mitochondria – harvesters of sunlight energy from food We normally see our metabolism of food as the ultimate source of our mitochondrial adenosine triphosphate (ATP). However, if we look a little deeper, it is actually photons of sunlight (through photosynthesis) that are embedded in organic (carbon-containing) compounds, which then become our food. It is incredible to think that the trillions of mitochondria in our body are pumping us full of sunlight energy – every single second. The scientific detail of energy production in mitochondria can distract us from the startling reality of what is really occurring. Essentially, sunlight energy from plant photosynthesis is being removed from our food, in the form of high-energy electrons. This takes place within mitochondria in order to generate our own energy. Specifically the mitochondrial co-enzymes NAD+ (nicotinamide adenine dinucleotide (oxidized)) and FAD (flavin adenine dinucleotide) capture 30

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the sunlight-charged electrons from food and use these electrons to add hydrogen to form NADH (nicotinamide adenine dinucleotide (reduced)) and FADH2 (flavin adenine dinucleotide (reduced)), which are in turn used to synthesize ATP in a process called oxidative phosphorylation.

THE SUNLIGHT ENERGY RELAY RACE Photons from sunlight  [photosynthesis in plants]  creation of macro-nutrients in plants  electrons from food (i.e. glucose, amino acids and fatty acids)  [NAD+, FAD]  add hydrogen  [NADH, FADH2]  oxidative phosphorylation  ATP

The addition of high-energy electrons and hydrogen to a compound is called reduction. The reverse is called oxidation. (It can seem counterintuitive that the addition of high-energy electrons is called reduction!)

Reduction: the addition of high-energy electrons and hydrogen to a compound. Oxidation: the removal of high-energy electrons and hydrogen from a compound.

The importance of water

In this whole cycle of energy, from photosynthesis to mitochondrial energy, water is the donor of both electrons and hydrogen. Photons of sunlight energy effectively split water molecules to provide the electrons and hydrogen, which then bind atmospheric carbon dioxide to make the organic (carbon-containing) compounds essential for life. Without this careful ‘sunlight powered’ addition of hydrogen to carbon, life as we know it could not exist. Organic compounds are embedded into plants and animals, which in turn become our sources of food and energy. We break down food to release the ‘sunlight charged’ electrons and hydrogen for the reduction of NAD+ and FAD prior to their arrival at mitochondria for oxidative phosphorylation. In mitochondria 31

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our inhaled oxygen (the original waste product of photosynthesis) recombines with hydrogen (following ATP synthesis) to once again become a water molecule. In this way, sunlight energy is neatly shuttled through food, to be delivered to every single mitochondrion of our being. Oxidative phosphorylation (the oxidation of nutrients to produce ATP – see the section ‘The three mitochondrial energy processes’ below) neatly brings all these components back together to make water and ATP. ATP is the final carrier of the sunlight energy baton, in this wonderful sunlight energy relay race.

Figure 3.1 The sunlight energy relay race

Pyruvate – at a metabolic crossroad Respiration (i.e. energy production) in cells can be either aerobic or anaerobic. The compound pyruvate is key to deciding whether a cell works with or without oxygen. A cell can work perfectly well with or without oxygen. Aerobic respiration (with oxygen) is preferred for energy production. Anaerobic respiration (without oxygen) is preferred for inflammation and proliferation. Pyruvate is created from glucose in a process known as glycolysis, and the ultimate fate of the pyruvate will determine whether a cell works with or without oxygen: If pyruvate is shunted off toward lactic acid synthesis, cell respiration will be anaerobic. If pyruvate is transported into mitochondria, then cell respiration will be aerobic. Outside a mitochondrion, pyruvate effectively finds itself at a metabolic crossroad – which way should it go? In normal metabolism,

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pyruvate should ideally take the path to be transported into mitochondria (via the mitochondrial pyruvate carrier, MPC). This allows the TCA (tricarboxylic acid) cycle to kick into action, and ultimately energy production via oxidative phosphorylation. The TCA cycle, also known as the Krebs cycle or the citric acid cycle, is a series of chemical reactions that are key to aerobic respiration in cells. The MPC acts as a doorway to mitochondria and aerobic respiration. The correct operation of the MPC is absolutely vital to protect a cell from excessive anaerobic respiration.

ANAEROBIC RESPIRATION AND THE WARBURG EFFECT Tumour cells preferentially choose anaerobic respiration, something that Otto Warburg noted in the early part of the 20th century. The shift toward anaerobic respiration in cancer is now known as the Warburg effect in recognition of his insightful work in this field. Kidney, colon, lung, bladder, ovarian and brain cancers have all been found to have reduced expression of MPC. The most striking effect of MPC loss is seen in ovarian cancer where there is a 60–80 per cent loss of MPC gene expression (Schell et al. 2014). Anaerobic respiration isn’t all bad – it’s an essential component of growth, and inflammation and wound healing. However, growth has to be within limits, wounds need to heal and inflammation should resolve itself, to avoid the risk of excess proliferation and growth. On the other hand, up-regulated MPC expression is seen in obesity and type 2 diabetes where pyruvate is used to increase blood sugar via gluconeogenesis (the generation of glucose from non-carbohydrate carbon substrates) (Gray et al. 2015). Thus, a correctly balanced MPC expression is crucial to health.

Once through the mitochondrial doorway of the MPC, pyruvate has to cross its next hurdle. In its quest for energy, pyruvate now has to navigate its way through the three enzymes of the pyruvate dehydrogenase complex (PDC). The output of PDC is acetyl-CoA, one of the raw materials required to kick-start the TCA cycle.

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Glycolysis Pyruvate

O u te r

m i to c h o

Mitochondrial pyruvate carrier (MPC)

ndrial membrane

Inner mitochondrial membrane

Pyruvate dehydrogenase complex (PDC) Acetyl-CoA

The tricarboxylic acid (TCA) cycle Figure 3.2 The mitochondrial pyruvate carrier is an essential mechanism which allows energy-charged molecules to enter into mitochondria

The end product of glycolysis is pyruvate. Pyruvate has to enter through the inner mitochondrial membrane via the mitochondrial pyruvate carrier (MPC). Once in the mitochondrial matrix, pyruvate is metabolized to acetyl-CoA by the pyruvate dehydrogenase complex (PDC). Acetyl-CoA is then free to enter the tricarboxylic acid (TCA) cycle.

The three mitochondrial energy processes Energy production in mitochondria relies on three different processes to provide energy from dietary or stored carbohydrate, fat and protein. As explored below, the three processes are: 1. The TCA cycle – also known as the citric acid cycle or Krebs cycle – which is key to aerobic respiration in cells. It utilizes acetylCoA (created from the metabolization of pyruvate) and produces reduced FADH2 and NADH which become electron donors in the electron transport chain. 2. Oxidative phosphorylation (OXPHOS) within the electron transport chain, in which nutrients are oxidized to produce energy. 3. β-Oxidation – the breakdown of fat to provide energy in mitochondria. 34

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1. The TCA cycle

The 1953 Nobel Prize for Physiology or Medicine was jointly won by Hans Adolf Krebs ‘for his discovery of the citric acid cycle’ and Fritz Albert Lipmann ‘for his discovery of co-enzyme A and its importance for intermediary metabolism’ (Kresge et al. 2005, p.165). Both men made huge advances in the quest to unlock the secrets of how energy production occurs within mitochondria. Pyruvate NADH Acetyl-CoA NADH

Citrate NADH

FADH2 NADH

Figure 3.3 The TCA cycle

Acetyl-CoA enters the TCA cycle where the enzyme citrate synthase converts it to citrate, then on to other metabolites. Further steps in the TCA cycle reduce vitamin B3- and vitamin B2-dependent NAD+ and FAD to NADH and FADH2. NAD+ and FAD are like the ‘hod carriers’ of the energy world. They shuttle the energy ‘bricks’ of hydrogen ions (protons) and high-energy electrons from the TCA to the electron transport chain (ETC). Reduced FADH2 and NADH subsequently become electron donors in the ETC.

Synthase: an enzyme that acts as a catalyst to help synthesize biological compounds.

2. Oxidative phosphorylation within the electron transport chain

The electron transport chain (ETC) can be explained more simply as a pump that pumps protons/hydrogen ions into the mitochondrial intermembrane space. The pumps are powered by the energy from

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high-energy electrons supplied by NADH and FADH2. Remember, NADH and FADH2 are carrying what was originally sunlight energy captured in food. The ETC is a highly efficient and intricate way of harvesting this sunlight energy to make ATP.

Protons – H+

Protons – H+

Cy

Inner mitochondrial membrane

CoQ10

Complex I

to c h

Protons – H+

Protons – H+

rome c

CoQ10

Complex III

Protons – H+

Complex II

Complex IV

ATP synthase (Complex V)

NADH

NAD+

Succinate

Fumarate

H2O

½O2

ADP

Figure 3.4 The electron transport chain

In oxidative phosphorylation enzymes are used to oxidize the end products of macronutrients (carbohydrate, protein and fat), which releases energy used to produce ATP. This occurs in the electron transport chain (ETC) via four complexes (an enzyme complex is an enzyme unit formed from multiple protein subunits) and ATP synthase, all embedded in the inner mitochondrial membrane. NADH and FADH2 from the TCA cycle and act as electron donors for the ETC. Complexes I, III and IV use the energy created by the electron donors to pump protons (hydrogen ions) into the intermembrane space, creating a proton electrochemical gradient. Protons flow back into the mitochondrial matrix through ATP synthase (Complex V) to generate the energy required to make ATP from ADP and Pi (inorganic phosphate). Complex II runs in parallel with Complex I, using FADH2 and succinate from the TCA cycle, to reduce ubiquinone to ubiquinol. Electrons from Complex IV are finally transferred to oxygen. NADH: nicotinamide adenine dinucleotide (reduced) NAD+: nicotinamide adenine dinucleotide (oxidized) ATP: adenosine triphosphate ADP: adenosine diphosphate CoQ10: coenzyme Q10

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Enzyme complex: an enzyme unit formed from multiple protein subunits.

Once in the intermembrane space, the hydrogen ions re-enter the mitochondrial matrix and provide the power for ATP synthase to convert ADP to ATP. The sunlight energy is held within the phosphate bond of ATP. Protons – H+ Reservoir of water to drive electric turbine Hydroelectric power station

Protons – H+

Protons – H+

Protons – H+

Protons – H+

Inner mitochondrial membrane

ATP synthase

Energy ADP

ATP

Figure 3.5 Hydroelectric dam vs ATP synthase

The intermembrane space and mitochondrial matrix are similar to the upper and lower reservoir of a hydroelectric dam. The flow of hydrogen ions/protons through ATP synthase to generate ATP resembles water driving a hydroelectric turbine.

A useful analogy for the electron transport chain is to liken it to a hydroelectric dam. In many hydroelectric dams, water is pumped slowly up to a reservoir above the dam. When energy is needed, the dam is opened to allow water to spin a turbine to generate energy. The complexes of the electron transport chain are like (and effectively are) solar-powered pumps. The protons in the intermembrane space are like the water in the dam. The turbine that produces electricity in the dam is like ATP synthase, the turbine-like enzyme in mitochondria which produces our ATP. ‘Uncoupling proteins’ are embedded alongside the ETC in the inner mitochondrial membrane and are important in helping to 37

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prevent free radical damage to cells during ATP synthesis – specifically, such uncoupling proteins act to prevent an excess of protons filling the intermembrane space. If the charge rises too high, this may lead to electrons becoming displaced from the ETC. If released prematurely from the ETC, the electrons may bind to oxygen within the mitochondrial matrix, leading to damaging superoxide radical formation. The proton charge directly corresponds to superoxide production, and therefore uncoupling proteins become an important safety-release valve (Divakaruni & Brand 2011). An intermembrane space with excess protons can be likened to a crowded commuter train. Passengers should ideally be getting on and off at the right stops, arriving fully charged up and energetic for work. However, imagine what a disaster it would be if the doors burst open mid-journey, through overcrowding. A mitochondrion can experience similar overcrowding when a Western diet continually overwhelms it with excess calories. Superoxide can be seen as disgruntled passengers spewing out of the electron transport chain! As well as being a damaging oxygen radical in its own right, superoxide can form a more toxic radical by diffusing with nitric oxide to form peroxynitrite. Peroxynitrite can inhibit Complexes I and II of the ETC and negatively affect ATP synthase (Valez et al. 2013). Excess peroxynitrite can have disastrous effects on mitochondrial function and integrity. The bacterial origins of mitochondria and plant chloroplasts make them both extremely vulnerable to antibiotics. Plants and insects, along with humans, are species from the mitochondrion-containing Eukarya domain of life. If a compound damages the mitochondria or chloroplasts of plants and insects, it is highly likely to be harmful to our own mitochondria (X. Wang et al. 2015). In addition to overuse of antibiotics by the medical profession, farming adds very high levels of antibiotic residue to ground water. Antibiotics are used as growth promoters in farm animals, but the damage to human mitochondria and environment is vastly underestimated. In addition to antibiotics, the herbicide paraquat and insecticide rotenone (used in organic farming) have damaging effects on Complex I of the ETC (Cochemé & Murphy 2008; Li et al. 2003).

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3. β-Oxidation

In 1904, Georg Franz Knoop discovered the steps required for β-oxidation of fatty acids in mitochondria. Ingeniously, he achieved his discovery by feeding dogs both even and odd carbon chains of fatty  acids  and measuring the resulting metabolites (Houten & Wanders 2010). β-Oxidation of fatty acids is the prime source of ATP for the liver, heart and skeletal muscle. For example, the heart depends on the β-oxidation of fatty acids for 60 to 90 per cent of its energy needs. During fasting, β-oxidation of fatty acids becomes an important energy source in all tissues except the brain. Although the brain cannot directly use fatty acids as an energy source, the liver produces ketone bodies which can be used for energy by the brain and all other tissues (Houten & Wanders 2010).

β-Oxidation: the breakdown of fatty acids to provide energy in mitochondria.

FATTY ACIDS Fatty acids are made from chains of carbon with hydrogen attached. A saturated fatty acid occurs when two hydrogen atoms are connected to each carbon atom within the fatty acid. A polyunsaturated fatty acid occurs when only one hydrogen atom is connected to each carbon atom, leaving one carbon bond free to double bond with adjacent carbon atoms within the fatty acid. A monounsaturated fatty acid occurs when there is only one double carbon bond in the whole of the carbon chain of the fatty acid. ‘Even chain’ and ‘odd chain’ refer to the number of carbon atoms within the structure of the fatty acids. ‘Even chain’ and ‘odd chain’, chain length, and unsaturated, polyunsaturated and monounsaturated fatty acids all have widely different effects on human metabolism.

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Medium-chain fatty acids, such as caproic and caprylic acid, are able to diffuse into mitochondria without a carrier protein. Long‑chain fatty acids need to be actively transported across both outer and inner mitochondrial membranes by a mechanism known as the carnitine shuttle. Long chains of fatty acids undergo several cycles of β-oxidation to snip the fatty acid into ‘bite-size’ chunks for mitochondria. Even-chain fatty acids produce one molecule of acetyl-CoA, NADH and FADH2 with each cycle of oxidation. When the fatty acid chain is eventually dismantled, acetyl-CoA, NADH and FADH2 are then ready for entry into the TCA cycle and electron transport chain (Houten & Wanders 2010). Odd carbon chains are metabolized in a similar way, except that the last cycle results in propionyl-CoA rather than acetyl-CoA (Jenkins et al. 2015). Unsaturated fatty acids require an extra enzyme to deal with the unsaturated double bonds (Houten & Wanders 2010). An interesting discovery regarding even and odd chains of fatty acids is that increased blood concentrations of even chains of fatty acids have been linked to increased risk of coronary heart disease, whilst the reverse is true for odd chains of fatty acids (Jenkins et al. 2015). Palmitic acid is an example of an even-chain saturated fatty acid which has been linked to coronary heart disease. Palmitic acid is found in animal products, coconut oil and palm oil. Palmitic acid is also made within our own cells from citric acid/acetyl-CoA exported from mitochondria. Heptadecanoic acid is an example of an odd-chain saturated fatty acid found in fish and dairy products. Heptadecanoic acid is also made within our intestinal tract from the fermentation of dietary fibre. Heptadecanoic acid can help protect against type 2 diabetes and heart disease (Weitkunat et al. 2017). A possible explanation for the negative effects of the even long‑chain fatty acid, palmitate, is that it can bind to proteins of the innate immune system and act as a promoter of inflammation (Chesarino et al. 2014). Inflammation, in turn, increases the endogenous synthesis of palmitate. (The starting point for internal palmitate synthesis is citrate from mitochondria.) Internal palmitate synthesis is essential for the manufacture of cell membrane phospholipids, protein modification and lung surfactants (supports lung aveoli function). Some 20–30 per cent of all body

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saturated fatty acids (SFAs) are as palmitate, demonstrating that palmitate is an absolutely vital lipid. However, poor diet and lifestyle and insufficient polyunsaturated fatty acid (PUFA) consumption can lead toward excess palmitate synthesis associated with lipid and blood sugar irregularities and inflammation (Carta et al. 2017). Fatty acids are transported in and out of mitochondria and through cycles of β-oxidation as esters, which need a molecule of coenzyme A (CoA) to function. CoA is a pantothenic acid (vitamin B5)dependent coenzyme.

More ways into the TCA cycle than just acetyl-CoA Many carbon skeletons of amino acids can be transformed into intermediates of the TCA and can enter the cycle. Amino acids that are metabolized to acetyl-CoA or acetoacetyl-CoA are known as ketogenic amino acids because they can potentially be further transformed into ketones or fatty acids. Amino acids that are metabolized into α-ketoglutarate, pyruvate, oxaloacetate, succinyl-CoA or fumarate are known as glucogenic (Berg et al. 2002).

Carbon skeleton: the compound that remains after ammonia has been removed from an amino acid.

Along with lactate and glycerol, the carbon skeletons from glucogenic amino acids can be used as substrates for gluconeogenesis, to provide an internal source of glucose in the post-absorptive state. The liver and the kidneys are the two main sites of gluconeogenesis, followed by the intestines.

Gluconeogenesis: the generation of glucose from noncarbohydrate carbon substrates.

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Surprisingly, after an overnight fast, the kidneys can supply as much as 10 per cent of total body glucose needs from gluconeogenesis (Gerich 2010). In obesity and type 2 diabetes there is an increase in protein breakdown and gluconeogenesis, as insulin resistance leads to blocks in normal energy-producing pathways (Chevalier et al. 2006).

The magic of soluble fibre In the intestine, the short-chain fatty acids propionate and butyrate, produced by the fermentation of soluble fibre, can both help initiate intestinal gluconeogenesis. Activation of intestinal gluconeogenesis has been shown to be an important factor in helping to control glucose metabolism and weight management. Although it seems counter-intuitive, glucose produced by intestinal gluconeogenesis has the beneficial effect of inhibiting liver gluconeogenesis. Excess liver gluconeogenesis is associated with insulin resistance type 2 diabetes (De Vadder et al. 2016). This highlights the importance of soluble fibre consumption and a healthy microbiota (De Vadder et al. 2014).

Microbiota: a community of up to 100 trillion microbial cells, held mainly within the gastrointestinal tract. This microbial community are largely bacteria, but also consist of yeast, archaea and viruses.

The health benefits of soluble fibre and its fermentation to short‑chain fatty acids have been known for many years. Many practitioners describe how fibre slows down glucose absorption. However, what hasn’t been properly understood is how proactive in human health the fermentation products (butyrate and propionate) actually are. When produced in the intestines, they are actively triggering intestinal gluconeogenesis to help control blood sugar and protect against type 2 diabetes (De Vadder et al. 2016).

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Mitochondria – the starting point for internal fatty acid and cholesterol synthesis In the liver, insulin resistance can switch signals in mitochondria in a way that makes them produce fatty acids to excess. Such over-expression of the enzymes involved in fatty acid synthesis has been associated with type 2 diabetes and cancer (Menendez et al. 2009; Mounier et al. 2014). The prevention of this switch away from mitochondrial ATP synthesis towards fatty acid synthesis is now considered an important strategy in the fight against cancer. It all starts with citric acid and the choice between whether it remains in the TCA cycle (to make ATP) or, alternatively, is exported for fatty acid (and chlolesterol) synthesis. So this is another important metabolic crossroad.

Key points for practitioners Energy production is a requirement of every single one of our cells, and if this is compromised it can lead to a vast array of health conditions. The whole body (including the nervous system, heart, brain, muscle, liver and kidneys) requires energy in the form of ATP to function properly and maintain a state of optimum health. To support a healthy supply of ATP, think B vitamins, CoQ10, CDP‑choline, magnesium, taurine, medium-chain triglycerides, soluble fibre and vitamin E.

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4 Mitochondrial Dynamics

Look at any textbook drawing of mitochondria and it will usually be of a lone mitochondrion. However, this idea of mitochondria working in isolation to make adenosine triphosphate (ATP) is now outdated and extremely simplistic. It is now known that mitochondria form a web of interconnected organelles across an entire cell. Mitochondria continuously combine and divide in processes called fusion and fission, allowing these incredible organelles to change their shape and reform rapidly. Mitochondrial fusion and fission are considered to be absolutely essential for rapid repair or degradation of mitochondria. Fusion and fission can also be seen as a kind of mitochondrial ‘shape-shifting’ to enable mitochondria to meet cellular energy needs to the best of their ability. Mitochondria have a shelf life of between a few days and several weeks, depending on where they are working in the body. At the end of their useful life, mitochondria are digested and recycled by mitochondrial autophagy, also known as mitophagy. Autophagy is a term that means ‘self-eating’, and so mitophagy can therefore be defined as ‘self-eating of mitochondria’.

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Mitophagy allows a cell to dispose of underperforming mitochondria so that the efficiency and quality of mitochondria is maintained at the highest level possible. In many chronic health conditions mitophagy does not take place fully. This can mean that many mitochondria become dysfunctional and struggle to work way beyond their ‘best-by’ date. Low cellular energy and an increase in reactive oxygen species (ROS) can be the damaging result of dysfunctional, underperforming mitochondria.

Mitophagy: the self-digestion (autophagy) of mitochondria.

Fusion, fission and mitophagy are all essential proactive mitochondrial processes. They highlight the fact that good dietary health requires something more than getting enough antioxidants. Good health requires not just prevention from degeneration, it requires active regeneration. Mitochondria are not always static within a cell as they are often on the move to areas of energetic need. Moving mitochondria are more accurately called motile, travelling on miniature tracks known as microtubules. Mitochondria are neatly driven along microtubules by protein motors, to assist them in delivering ATP to all of the cell.

Fusion and fission Mitochondria undergo continual cycles of fusion and fission to help them maintain the quality and efficiency of all their vital functions. Fission and fusion highlight just how active mitochondria are in their own quality control. Mitochondria are a major source of ROS or oxidants within a cell. In addition, mitochondria are extremely vulnerable to excessive levels of ROS. Oxidant damage to mitochondrial proteins, lipids and DNA can result in mitochondrial dysfunction. Sufficient (but not excessive) antioxidants are vital to help keep our mitochondria running efficiently. However, antioxidants alone will not suffice; in fact antioxidants in excess may block some quality-control mechanisms, particularly if used too close to exercise (Ristow et al.

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2009).2 Mitochondrial fission, fusion and mitophagy are required to remove worn-out or damaged mitochondria. Fusion is the merging of mitochondria. The process results in tubular, elongated mitochondria, as several of these organelles fuse together to make a larger, single mitochondrion. Conversely, fission is the splitting up of a larger elongated mitochondrion and results in small spherical mitochondria as the mitochondrion divides into smaller organelles. Fission and fusion help make sure that when cells are dividing, during growth and mitosis, mitochondria are shared out evenly to both daughter cells. (Remember that cell division in normal tissue growth results in two daughter cells from each original.) Parent cells have to guarantee that both daughter cells receive an equal mitochondrial inheritance, or there will be trouble. If mitochondria are not shared equally, there could be an increased risk of a daughter cell being compromised due to insufficient ATP production. At the level of the whole organism, these mitochondria-depleted cells could undermine the function of tissue and organs during growth and repair. In mature cells, fission and fusion help a cell rapidly redistribute mitochondria when cellular energy requirements change (Morán et al. 2012; van der Bliek et al. 2013).

Mitosis: the process of DNA division that allows a growing cell to divide. As more cells grow and divide, increased cell numbers lead to the growth of related tissue. Mitosis allows a parent or mother cell to divide into two daughter cells.

Fusion enables the filtering and re-use of still viable mitochondrial components, and the removal of worn-out components, to help build a stronger pool of mitochondria (Ni et al. 2015). Larger-fused mitochondria are less likely to experience excess cellular stress and premature 2 In this study, entitled ‘Antioxidants prevent health-promoting effects of physical exercise in humans’, the authors concluded that supplemental ingestion of the antioxidants vitamin E and vitamin C could negate the insulin-sensitizing benefits of ROS induced by exercise. Mitochondrial ROS generated during exercise were found to activate the expression of genes relating to insulin sensitivity, mitochondrial synthesis, superoxide dismutase and glutathione peroxidase. 46

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degradation. Fused mitochondria tend to provide stable oxidative phosphorylation, which may benefit β-oxidation of fatty acids (Youle & Bliek 2012) since fatty acids cannot be metabolized anaerobically. Another major benefit of fused mitochondria is that they may be better protected against mitochondrial DNA (mtDNA) mutations, due to the sharing and therefore diluting of the effects of mtDNA mutations (van der Bliek et al. 2013). mtDNA encodes many electron transport chain proteins, so fusion can protect ATP supply by helping support mtDNA integrity. On the other hand, fusion can be problematic when excessively damaged mitochondria fuse with, and undermine, healthy mitochondria. This damaging process is called mitochondrial contagion (Dorn & Kitsis 2015). Mitochondrial contagion has the unfortunate effect of allowing damaged mitochondria to spread their dysfunctional components to healthy ones, in a similar way to a contagious disease. Although still in the early stages of research, mitochondrial contagion is thought to play an important role in the pathogenesis of familial (genetic) Parkinson’s disease (Bhandari et al. 2014). Mitochondrial contagion can occur when the quality of the overall mitochondrial population is low, and thus it becomes increasingly difficult to find well-functioning mitochondrial components to use.

Mitochondrial biogenesis

Fusion Mitophagy

Fission

Dysfunctional mitochondrion

Figure 4.1 Fusion and fission

Mitochondria undergo cycles of fusion (merging) and fission (splitting) to help ‘weed out’ dysfunctional components. Poorly performing mitochondria are then digested and degraded by mitophagy (self-eating of mitochondria). Newly generated mitochondria can enter this cycle via mitochondrial biogenesis. 47

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Mitochondrial biogenesis: a process that creates brand-new mitochondria. Mitochondrial biogenesis relies on both nuclear and mitochondrial DNA to help make the necessary proteins to be assembled into a brand-new mitochondrion.

Fission enables a mitochondrial quality-control check Fission of mitochondria allows for the splitting off of worn-out or damaged mitochondrial components so that they can be degraded and removed. Fission is at the front end of an essential mitochondrial quality‑control process which is continually seeking out ‘good’ mitochondria to keep, and ‘bad’ mitochondria to lose. During fission, the electrochemical charge on the surface of a mitochondrion is checked for ‘quality’ – the charge is known as the mitochondrial membrane potential. If the mitochondrial membrane potential is too low, the mitochondrion should not be allowed to fuse with another healthy mitochondrion and should be degraded via mitophagy (van der Bliek et al. 2013). Mitochondrial contagion can occur when the overall mitochondrial quality is low, as seen earlier.

Excessive fission can be problematic Cellular stress is produced by a wide variety of sources, including mitochondrial ROS (particularly if dysfunctional), raised inflammation, excessive cellular calcium and high blood glucose and free fatty acids. Cellular stress can also occur when there is insufficient antioxidant defences to counter normal levels of ROS. High levels of cellular stress can lead to lower-quality mitochondria, due to an increase in fission and a reduction in fusion. Excessive fission leads to smaller and less connected mitochondria that are more likely to produce reactive oxygen species and undergo apoptosis (programmed cell death) or mitophagy (Archer 2013; Solesio et al. 2012). Excessive mitochondrial fission plays a role in driving many of our most feared chronic illnesses.

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Neurodegeneration Excessive fission is believed to be an important mechanism driving the apoptosis of neurons in neurodegenerative diseases. Parkinson’s, Alzheimer’s and Huntingdon’s diseases all have been found to have imbalances in proteins that drive the fission process. It has been observed that mitoquinone (a mitochondrial-targeted antioxidant) can help prevent the damaging effects of increased fission in laboratory models of Parkinson’s disease (Solesio et al. 2012). Increases in mitochondrial fission are sometimes necessary, however. For example, greater fission improves the mobility of mitochondria at nerve terminals and synapses in the central nervous system. Frustratingly, the need to have mitochondria more mobile at a synapse makes them more vulnerable to accumulating excess calcium, and much less efficient at producing ATP (Perier & Vila 2012). Researchers are unsure why synaptic mitochondria are more vulnerable to calcium excess. One hypothesis is that smaller-fissioned mitochondria at a neuronal synapse have less calcium-carrying capacity, compared to larger-fused mitochondria, sited away from the synapse (Brown et al. 2006). The negative trade-off for increased synaptic mitochondrial mobility (from increased mitochondrial fission) is a more vulnerable and less efficient community of mitochondria. In Parkinson’s disease models, synaptic mitochondria can only tolerate 25 per cent reductions in ATP, before they display signs of pathology. Away from the central nervous system, however, mitochondria are far more robust and can tolerate 60 per cent reductions in ATP synthesis (Davey et al. 1998). The compromise in mitochondrial robustness for synaptic mobility highlights just how important it is to protect neuronal mitochondria in the race to reduce the risk of neurodegenerative disease.

Type 2 diabetes There are some major environmental inputs that can affect these processes. For example, exposing β-cells (the insulin-secreting cells in the pancreas) to high glucose and free fatty acids can lead to excessive

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mitochondrial fission with a resulting increase in small, vulnerable and fragmented mitochondria. Fragmented mitochondria are more prone to initiating apoptosis and therefore β-cell death. Normal pancreatic β-cells contain competent networks of elongated and fused mitochondria. In type 2 diabetes β-cell mitochondria are found to be disconnected, swollen and shorter than their healthy counterparts (Supale et al. 2012). As well as the direct effects of diabetes on a patient’s pancreas, there are many unforeseen effects of type 2 diabetes linked to mitochondrial fusion and fission. An example of this is how fusion and fission can affect the immune system. In the leukocytes (white blood cells) of diabetic patients, decreased fusion and increased fission can cause greater leukocyte adherence to blood vessel walls. The adhesion of leukocytes to blood vessel walls is an initiator of inflammation and dramatically increases the risk of cardiovascular disease (Diaz-Morales et al. 2016).

Breast cancer In the same way that fission allows for redistribution of mitochondria in dividing cells, fission allows breast cancer cells to spread and metastasize (invade tissue and organs) more easily. Fission allows for the redistribution of mitochondria to the leading edge of metastasizing breast cancer cells, causing greater energy production at these sites, and thus driving more rapid tumour growth (Zhao et al. 2013). It is highly likely that excessive mitochondrial fission will be found to be related to other cancers as further studies are carried out.

What can help to reduce excessive mitochondrial fission? Given that excessive mitochondrial fission can be a driver of so many chronic illnesses, protecting against excessive fission is essential for long-term health. The protein kinase AMPK (AMP-activated protein kinase) has been found to reduce the risk of excessive fission, by inhibiting the fission50

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initiating protein Drp1. AMPK happens to be an energy-sensing protein. This can be induced by calorie restriction, exercise and ketogenic diets.

AMPK (AMP-activated protein kinase): an energy-sensing protein induced by calorie restriction, exercise and ketogenic diets.

Supplementary resveratrol and acetyl-L-carnitine promote the activity of the anti-ageing protein SIRT3 in mitochondria. In turn SIRT3 can also inhibit mitochondrial fission (Chen et al. 2015; Morigi et al. 2015). Thus induction of AMPK and SIRT3, via exercise, diets and certain supplements, has the potential to help prevent many degenerative health conditions, by bringing dysregulated mitochondrial fusion and fission back into balance. It is apparent from this chapter that fusion and fission are needed to regulate mitochondrial mobility, redistribution, quality control and repair. Losing this dynamic connection between mitochondrial fusion and fission can be a major factor in accelerated ageing, poor health and degeneration. Maintaining the balance between fusion and fission is absolutely essential for a long and healthy life.

Autophagy and mitophagy – self-digestion for longevity Autophagy is a term that means ‘self-eating’. It is a vital process that allows for the digestion and removal of worn-out cellular components to ensure the efficient and smooth running of a cell. Our neurons may have to last us a lifetime, but the contents of the neuron go through a regular autophagy ‘spring clean’ every few days, to keep the neuron functioning and to protect it against degeneration. Autophagy of mitochondria is called mitophagy. Mitophagy can therefore be defined as ‘self-eating of mitochondria’. Mitochondria need to be digested every few days, through mitophagy, to maintain a healthy mitochondrial population. The halflife of mitochondria in organs is: 51

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• liver: 1–2 days • heart: 5–6 days • brain and kidneys: approximately 24 days. (Galluzzi et al. 2008; Miwa et al. 2008)

The life of a mitochondrion is measured as a half-life rather than its full life, just because it’s often easier to measure with radioactive labels that are measured by half-lives. Radioactive labelling of mitochondria involves making some mitochondrial proteins radioactive in the laboratory, to enable their detection in mitochondria. It is assumed that when the measured radioactivity decreases by 50 per cent, the number of mitochondria will also have decreased by 50 per cent. It’s interesting that dietary restriction decreases the half-life of mitochondria. Shorter-living mitochondria are more efficient and can help improve the integrity of all mitochondria throughout the body. The opposite is true for dietary excess, also known as over-nutrition. Over-nutrition can increase the half-life of mitochondria, meaning that the mitochondrial pool will decrease in efficiency, as they are working beyond their optimum shelf life. Dietary excess leaves the body with far less time to fine tune mitochondria to peak efficiency. Mitochondrial fission enables worn-out mitochondrial components to be separated from functional mitochondrial components. A fissioned worn-out mitochondrion is then ready for recycling through mitophagy. The remaining functional fissioned mitochondria are then free to return and fuse with the cellular network of healthy mitochondria. Mitochondrial fission is needed for mitophagy to occur, but not to the high degrees that are found in chronic illnesses. Mitophagy is initiated when a worn-out mitochondrion is initially sequestered by a body called an autophagosome. It forms a double membrane which envelops the mitochondrion and transports it to fuse with an organelle called a lysosome (Shawgo 2009). The fused autophagosome and lysosome become the aptly named autophagolysosome, where contents such as mitochondria and other organelles are degraded by powerful enzymes (Yu et al. 2008). Mitophagy of mitochondria is a relatively new discovery and was initially met with strong resistance. The idea that the mitochondria would purposely digest themselves was a strange concept when John 52

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Lemasters first proposed the process in 2005. Lemasters suggested mitophagy to be non-random, but also an essential quality-control mechanism. In this way, the removal of worn-out mitochondrial components could form a major part of a cell and organism’s anti‑ageing strategy (Lemasters 2005). Although mitophagy is seemingly a minor discovery in the biological world, the larger victory is the acceptance of a process to be non‑random. Why is acceptance of non-random processes so important? Well, it opens up a deeper understanding of the innate intelligence of how mitochondria function within a living system – it opens up an understanding of how living systems actively defend against ageing, and it potentially gives practitioners more subtle ways to address chronic health issues, by nurturing and working with intelligent processes. But how can these intelligent processes be nurtured?

Nurturing regeneration We’ve discussed how it is essential for mitophagy to occur, to help maintain a healthy stock of mitochondria within a cell. Mitophagy occurs more frequently when insulin and cellular energy levels are low. A major sensor of low energy is AMPK, as discussed earlier in the chapter. AMPK is able to sense when ATP and nicotinamide adenine dinucleotide (reduced) (NADH) are low and AMP and nicotinamide adenine dinucleotide (oxidized) (NAD+) are high. AMPK signals to our metabolism that the body is lacking in energy, or is in energetic stress. Surprisingly, for a healthy person, energetic stress is a good place to be! AMPK acts to initiate processes which replenish ATP levels, trigger anti‑ageing strategies and help regenerate the body. In a sense, AMPK is like a fuel gauge, switching to reserve fuel supplies when ATP and NADH fuel tanks are running low. When the energy fuel tanks are low, AMPK initiates a full-on efficiency drive that makes sure every mitochondrion is pulling its weight. AMPK activates mitochondrial fission (normal, not pathological), biogenesis, mitophagy and fatty acid oxidation. Simultaneously, AMPK decreases all non-essential ATP-consuming processes, such as the 53

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synthesis of fatty acids, proteins and cholesterol (Hardie et al. 2014; Zhang & Lin 2016). Exercise, calorie restriction and a ketogenic diet may introduce some degree of energetic stress to enable the positive mitochondrial supportive actions of AMPK (Hardie 2013; McDaniel et al. 2011; O’Neill et al. 2013). These dietary strategies help drain the energy fuel tanks of ATP, NADH and acetyl-CoA, to enable AMPK to embark on its anti‑ageing, regenerative efficiency drive.

AMPK AND INSULIN Insulin resistance suppresses AMPK (Ruderman et al. 2013), meaning that AMPK will be poorly expressed in metabolic syndrome and type 2 diabetes. Decreased expression of AMPK will lead to reduced fusion, fission and mitophagy, and therefore mitochondrial dysfunction will, sadly, be inevitable. For people with insulin resistance, metabolic syndrome or type 2 diabetes, the loss of AMPK expression may mean that they may not be able to reap the benefits of calorie restriction, exercise and ketogenic diets. In fact it may be dangerous for them, since they may not be able to access alternative fuel sources when energy levels drop. A better strategy would be to work on improving the insulin sensitivity first. People have often been advised to eat little and often when they have blood sugar swings – without addressing insulin resistance issues that are the cause of blood sugar imbalances. Improvements in insulin sensitivity (through diet, exercise or supplementation) will allow a person to tolerate lower ATP and permit mitochondrial quality-control mechanisms to function. This is not to say that calorie restriction, exercise and ketogenic diets should never be attempted by people with insulin resistance, metabolic syndrome or type 2 diabetes as there is a mounting body of evidence in support of these activities. What is suggested here is that a person avoids a ‘gung-ho’ approach and acknowledges the limitations of their present health condition. For example, they start with a low GL diet rather than immediately trying a ketogenic diet/fasting, and build up exercise levels gradually. 54

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The supplement α-lipoic acid is an activator of AMPK and can help improve insulin sensitivity. In fact it may be through its activation of AMPK that α-lipoic acid reduces insulin resistance (Woo et al. 2005). Rooibos tea is another and surprising activator of AMPK that can have positive effects on insulin resistance and mitochondrial function (Coughlan et al. 2014). The anti-diabetic drug metformin is an agonist of AMPK but, worryingly, the drug also inhibits mitochondrial oxidative phosphorylation, leading to increased ROS generation (Bridges et al. 2014).

Mitophagy is neuroprotective Although the structure of a neuron has to last a lifetime, the organelles within the neuron have to be continually turned over to maintain the integrity of the neuron. A neuron is in a continual ‘spring clean’ state, refurbishing the contents of the neuron every few days. Neurons are known as post-mitotic cells, in that they cannot undergo mitosis and proliferate like most of our cells. One thing that post-mitotic neurons can do is recruit stem cells to allow some degree of repair (Campisi & d’Adda di Fagagna 2007). Generally though, the neuronal population a person possesses now is dependent on the state of their nervous system from birth. Neurons rely almost exclusively on mitochondria for cellular energy, and it is now becoming apparent that failure of mitochondrial quality control and mitophagy can play a major role in the pathogenesis of neurodegenerative disease. Parkinson’s, Alzheimer’s, Huntingdon’s and motor neurone diseases are all thought to be linked to impaired mitophagy (Amadoro et al. 2014).

Mitochondrial motility (mobility) It’s a little-known fact that a mammalian cell contains a cytoskeleton, a scaffold-like structure that gives a cell its unique shape and form. The ‘scaffold’ of the cytoskeleton is made up of microtubules, the bar‑like 55

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fibres woven into a fine network across a cell. The microtubules are also used as microscopic railway tracks, to help transport mitochondria and other components around a cell. It’s another surprise that mitochondria actually have their own little engines to chauffeur them up and down the cytoskeleton. These engines are the protein motors kinesin and dynein which transport mitochondria away from the nucleus (anterograde) and toward the nucleus (retrograde) respectively.

Anterograde: movement away from the nucleus. Retrograde: movement toward the nucleus.

Retrograde – to the nucleus

Anterograde – to the synapse

Mitochondrion attached to a protein motor

Microtubule

Figure 4.2 Mitochondrial motility

In neurons (and many other cells), mitochondria are motile (mobile). To get to areas of energetic need, mitochondria are driven by protein motors along cytoskeletal tracks called microtubules.

In neurons, most mitochondria are produced within the cell body but are delivered by anterograde motion, along the axon, to areas of energetic need (Liu et al. 2012). Poor mitochondrial motility is felt more acutely in the nervous system due to the relatively large axon length of neurons. Neuronal mitochondria are like the marathon runners of the mitochondrial world! 56

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In Alzheimer’s disease, the number and length of microtubules in pyramidal neurons are heavily affected by poor upkeep of the cytoskeleton. A signature of Alzheimer’s disease is the functional alteration (specifically in hyperphosphorylation) of tau proteins, which act as the maintenance engineers of the cytoskeletal scaffold. Tau proteins normally bind to, and stabilize, microtubules, and their loss leads to the degradation of microtubule tracks. Without the microtubule tracks and roads on which to deliver their highly valued mitochondrial goods, energy distribution in neurons is hugely compromised (F. Zhang et al. 2015). It is extremely difficult to test compounds for their effects on the human brain, so much of the investigative work has to be carried out on cell cultures that try to closely mimic the human brain. In the laboratory, curcumin has been demonstrated to help prevent tau hyperphosphorylation (Huang et al. 2014). Therefore, curcumin may have potential to maintain mitochondrial motility in neurons that have been compromised in Alzheimer’s disease. In a similar way to Alzheimer’s disease, disorganized networks of microtubules have been found to occur in Parkinson’s disease. The loss of these microtubule tracks in Parkinson’s disease leads to a toxic and catastrophic accumulation of damaged mitochondria and protein aggregates. This toxic build-up of compromised cell components can eventually lead to the death of dopamine-producing neurons, the primary signature of Parkinson’s disease (Esteves et al. 2014).

Kissing, nanotunnelling and tunnelling nanotubes An adult cardiac muscle cell (cardiomyocyte) contains roughly 6000 mitochondria which constitute around 40 per cent of the cell volume. Unlike many other cells, cardiomyocyte mitochondria are not motile and cannot undergo fusion and fission to help maintain a healthy mitochondrial population.

Cardiomyocyte: an adult cardiac muscle cell.

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Cardiomyocyte mitochondria have evolved an ingenious way to overcome the limitations of their static nature. They achieve this by forming one large interconnected network of mitochondria per cell. Adjacent mitochondrion pairs literally ‘kiss’ to exchange precious contents. Non-adjacent mitochondria form nanotubular tunnels, or nanotunnels, to exchange contents at a distance. The contents of a single mitochondrion can disperse over a whole cardiomyocyte in the space of ten hours (X. Huang et al. 2013). There is an amazing array of regenerative and repair systems in place to help maintain mitochondria at their peak efficiency. Healthy cells can help rescue cells at risk from apoptosis (programmed cell death) by providing an injection of healthy mitochondria. This selfless action by healthy cells can be seen as a ‘mitochondrial kiss of life’ to a struggling cell. Tunnelling nanotubes (TNTs) are formed by stressed cells as a way of inviting healthy cells, such as stem cells, to donate healthy mitochondria and prevent cell death. TNTs can help rescue slowgrowing or post‑mitotic cells, such as cardiomyocytes and neurons. The down side of TNTs is that they may also rescue cancer cells from apoptosis, potentially undermining cancer treatment and therapy (Wang & Gerdes 2015). Stem cell

Stressed cell

Transfer of healthy mitochondria from stem cell to stressed cell Figure 4.3 Tunnelling nanotubes support stressed cells with new mitochondria

Tunnelling nanotubes (TNTs) are formed by stressed cells as a way of inviting stem cells to donate their healthy mitochondria. The injection of healthy mitochondria can help prevent the death of stressed cells.

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Mitochondrial biogenesis The creation of brand-new mitochondria is known as mitochondrial biogenesis. Mitochondrial biogenesis requires the tight co-ordination of both nuclear and mitochondrial DNA before biogenesis can begin. The master co-ordinator of mitochondrial biogenesis is PGC-1α. PGC-1α is a complex acronym that stands for ‘peroxisome proliferatoractivated receptor-γ (PPARγ) co-activator 1α’. It’s enough to understand that PGC-1α is an essential co-activator of brand-new mitochondria and not go too deep into the scientific meaning of the acronym. Exercise leads to an increase in PGC-1α levels, particularly in skeletal muscle. PGC-1α enables cells and tissue to respond to the demand for  more energy by increasing the biogenesis of new mitochondria (Yan et al. 2012). PGC-1α co-activates several transcription factors necessary for mitochondrial biogenesis to occur, including peroxisome proliferatoractivated receptors (PPARs), nuclear respiratory factors (Nrfs) and the transcription factor of activated mitochondria (TFAM) (Yan et al. 2012). Transcription factors are cellular compounds which pass information for gene transcription directly to the DNA. PGC-1α has to relocate from the cytoplasm to the nucleus to trigger mitochondrial biogenesis. Exercise helps to enable this essential relocation of PGC-1α (Jung & Kim 2014).

Transcription factor: a cellular compound which passes information for gene transcription directly to the DNA.

In addition to relocation, PGC-1α has to have two important modifications before it is active. AMPK adds a phosphate (to phosphorylate) and the enzyme SIRT1 removes an acetate (to deacetylate) to activate the protein (Santos et al. 2014). After relocation and modification, PGC-1α is ready to initiate mitochondrial biogenesis. As mentioned before, exercise, calorie restriction and a ketogenic diet may introduce some degree of energetic stress to enable the positive

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mitochondrial supportive actions of AMPK. One of these supportive AMPK actions is mitochondrial biogenesis via PGC-1α activation (Hardie 2013; McDaniel et al. 2011; O’Neill et al. 2013). Samples of muscle from people with insulin resistance have been found to contain 30 per cent less mitochondria than healthy individuals. Restoring PGC-1α to normal levels has been found to improve glucose balance, insulin resistance, and mitochondrial function and number (Santos et al. 2014). The activation of TFAM by PGC-1α is needed so that mtDNA can respond to PGC-1α and initiate mitochondrial biogenesis (Santos et al. 2014).

PGC-1α

TFAM

Mitochondrial biogenesis

Figure 4.4 PGC-1α and mitochondrial biogenesis

The activation of TFAM by PGC-1α is needed so that mtDNA can respond to PGC‑1α and initiate mitochondrial biogenesis. PGC-1α: peroxisome proliferator-activated receptor co-activator 1α TFAM: transcription factor of activated mitochondria

As we age, mitochondrial biogenesis starts to decline through loss of TFAM function. Calorie restriction may be able to reverse this process, and restore mitochondrial biogenesis. Therefore, restoration  of mitochondrial biogenesis could be an important anti-ageing benefit of calorie restriction in humans (Picca et al. 2013). The synergistic actions of resveratrol (a polyphenol from grapes, berries, nuts and cocoa) and equol (a soy metabolite from gut fermentation) have been found experimentally to exert a beneficial effect on mitochondrial health and function. These two natural compounds display the ability to increase mitochondrial biogenesis to a greater degree when supplemented together (Davinelli et al. 2013).

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In this chapter we have seen that mitochondria are far more mobile, dynamic and proactive than most biology textbooks would lead us to believe. They go to extreme lengths to maintain their integrity, transport themselves to areas of energetic need and even support each other when necessary.

Key points for practitioners It is now understood that mitochondria have to do far more than passively reside in a cell, quietly producing ATP. Mitochondria are highly dynamic, travelling to areas of energetic need and tirelessly working to maintain optimum quality and efficiency. As we age, it becomes more and more difficult for mitochondria to work efficiently, leading to degenerative conditions of the heart, bone and nervous system. To support mitochondrial quality and dynamics, think exercise, calorie restriction, resveratrol, curcumin, green tea and magnesium.

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5 Maintaining Allostasis

Mitochondria have to be flexible enough to help maintain an appropriate energy supply, at every single moment of our lives. Just like a multi-fuel stove, they have to be able to rapidly adapt to different fuel supplies – without complaint! Whether metabolizing protein, fat or carbohydrate from food or body stores, mitochondria have to be able to change their set-up to suit whatever fuel is delivered to their ‘mitochondrial stove door’. As seen in Chapter 3, the metabolic fuel delivery could be pyruvate, acetyl-CoA or ketones, and oxygen may be plentiful or scarce. Furthermore, the fuel could be used to burn for energy (catabolism), or to provide the raw materials for building (anabolism). Appropriate fuel burning/building decisions need to be rapidly executed, moment by moment, to match environmental challenges to energetic and bodily needs. However, when mitochondria become inflexible, and fail to adapt appropriately, then chronic illness can prevail. Essentially, type 2 diabetes, cardiovascular disease and metabolic syndrome can be considered diseases of metabolic inflexibility. A lifetime of calorie excess, lack of exercise and too many refined carbohydrates can cause insulin resistance.

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Insulin resistance can lead to the loss of metabolic flexibility and a struggle to adapt to an appropriate fuel supply. Adding to the difficulty, there may be too much building (anabolism) and not enough burning. Too much anabolism means too much growth and proliferation, with too many of the wrong kind of immune cells proliferating and driving inflammation.

The Randle cycle fuel choice: pyruvate or acetyl-CoA from fat? The Randle cycle, or ‘glucose–fatty acid’ cycle, allows for competition between different fuel sources, which cleverly allows for appropriate fuel choices from food and in the fasting state. The balance of insulin and glucagon (a hormone which releases a stored sugar called glycogen from the liver) helps to provide coarse control of fuel selection. Fine control of fuel selection for mitochondria is dependent on the fuel availability and tissue type. The output of the Randle cycle is acetyl-CoA (for the tricarboxylic acid (TCA) cycle), which can come from carbohydrate-derived pyruvate, or from fatty acids or ketones, depending on what fuel is available. In the cycle, pyruvate is metabolized through a series of enzymes, collectively known as the pyruvate dehydrogenase complex (PDC), generating acetyl-CoA, nicotinamide adenine dinucleotide (reduced) (NADH) and CO2. In fact the PDC is the largest enzyme complex in mammals (Constantin-Teodosiu 2013), highlighting just how important this key enzyme is as a doorway to energy production. It seems odd but acetyl-CoA, NADH and adenosine triphosphate (ATP) can also inhibit the PDC; just like a central heating thermostat, the PDC needs to know when there’s enough energy around and avoids wasting valuable resources. Mitochondrial PDC effectively has an ‘energy-stat’ (energy thermostat), which works in a similar way to a central heating thermostat. The energy-stat is made up of two enzymes: pyruvate dehydrogenase kinase and pyruvate dehydrogenase phosphatase. The kinase switches off the PDC when acetyl-CoA, NADH and ATP are plentiful: more

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calories will not turn the PDC ‘boiler’ back on! Increasing levels of coenzyme A (CoA), nicotinamide adenine dinucleotide (oxidized) (NAD+) and adenosine diphosphate (ADP) signal a drop in energy; then the phosphatase switches the PDC boiler back on again (Pietrocola et al. 2015). To reiterate, this neat control mechanism allows the PDC to run if there is sufficient pyruvate or low energy, but to be inhibited if there is insufficient pyruvate or high levels of acetyl-CoA and NADH. Importantly, the sensitivity of the PDC to the presence or lack of pyruvate allows mitochondria to switch from carbohydrate burning to fat burning. Acetyl-CoA from β-oxidation and ketosis take over and switch off the PDC when there is insufficient pyruvate to run the complex. Other activators of the PDC are insulin, exercise, calcium and magnesium. Calcium helps to keep the PDC in an active state during muscle contractions. Calcium and glycogen are released from muscle stores to supply mitochondrial PDC with the pyruvate and calcium needed for contraction. Therefore, one benefit of exercise is the release of calcium from cellular stores to help activate the PDC (ConstantinTeodosiu 2013). Pyruvate

Calcium, magnesium, insulin

Pyruvate dehydrogenase phosphatase

GO

Pyruvate dehydrogenase kinase

STOP

ATP, acetyl-CoA, NADH

Pyruvate dehydrogenase complex

GO

STOP

Pyruvate, ADP, CoA, NAD+

ATP, acetyl-CoA, NADH

Acetyl-CoA

Figure 5.1 The Randle cycle

The Randle cycle is a neat mechanism which allows mitochondria to choose the appropriate method to ‘burn’ either carbohydrate or fat. The cycle cleverly senses when there is sufficient mitochondrial energy and switches ‘off’. When energy levels drop, the cycle switches ‘on’, allowing the production of acetyl-CoA which will then enter the TCA cycle.

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Ageing, metabolic syndrome and metabolic inflexibility Both ageing and metabolic syndrome reduce our ability to maintain the PDC activation needed to burn pyruvate from carbohydrate sources. This is particularly noticeable in muscle where pyruvate is converted to lactic acid, as pyruvate is blocked from entering mitochondria. Insulin resistance plays a large role in this problem by acting to desensitize the PDC. The PDC depends on insulin signalling for its operation (Stacpoole 2012). As a person ages, the reduced activity of the PDC can lead to muscle fatigue and an increased risk of cancer and Alzheimer’s disease (Stacpoole 2012). It’s fine for the PDC to be switched off when pyruvate levels are low. However, if pyruvate levels are high and the PDC is still switched off, pyruvate has ‘nowhere to go’. A cell can convert pyruvate to lactic acid, but eventually the drop in pH from lactic acidosis will undermine the whole cell’s operation. A cell will effectively function anaerobically, even in the presence of ample oxygen. In addition to the problem of anaerobic respiration, poor functioning of the PDC in ageing and metabolic syndrome can lead to an increase in skeletal and cardiac muscle acetyl-CoA and NADH, derived from the β-oxidation of long-chain fatty acids. Remember, high ratios of acetyl‑CoA:CoA and NADH:NAD+ make it extremely difficult for the Randle cycle (the ‘glucose–fatty acid’ cycle) to shift back to pyruvate utilization. This increasing reliance on non-pyruvate acetyl-CoA is thought to contribute to more insulin resistance as metabolic syndrome progresses (Stacpoole 2012). Sufferers of chronic fatigue syndrome (CFS) also suffer with poor function of the PDC, leading to lactic acidosis and fatigue in their muscles and central nervous system. It is highly likely that a large number of symptoms of CFS sufferers are linked to an over-reliance on anaerobic respiration, due to problems with the PDC and mitochondria (Rutherford et al. 2016).

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Key points for practitioners The ability to choose between carbohydrate and fatty acids as fuel sources is a vital function of mitochondria. Confronted with dietary or stored carbohydrate and fat, mitochondria need to sense what is being presented and adapt their behaviour accordingly. The Randle cycle allows mitochondria exactly this flexibility. Ageing, metabolic syndrome, type 2 diabetes and fatigue can all be conditions where there is a struggle to select appropriate fuel sources for mitochondria. To support the Randle cycle, think magnesium, calcium, exercise, calorie restriction, B vitamins and α-lipoic acid.

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6 Acetyl-CoA A Vital Energy Source and Controller of a Cell

Acetyl-CoA is most well known for being the product of oxidation of pyruvate and fatty acids, but its actions within mitochondria, and the cell as a whole, are far more complex than is widely recognized. Living systems have evolved ingenious ways of providing multiple uses of the same molecule, and acetyl-CoA is no exception. In addition to supplying energy to the TCA (tricarboxylic acid), the  cellular and mitochondrial levels of acetyl-CoA act as markers for the energy status of the cell. This forms part of the ‘energy-stat’ (energy thermostat) described in the previous chapter, but can also be seen as a cellular and mitochondrial fuel gauge. Acetyl-CoA acting as a fuel gauge makes it an extremely valuable messenger for providing information about the present levels of cellular and mitochondrial energy (Pietrocola et al. 2015). Acetyl-CoA can effectively inform a cell when it has sufficient energy and then switch its activity toward the biosynthesis of fatty acids and support cell growth. Acetyl-CoA can also change the behaviour of mitochondria and the cell, by alternating the function of the genes and proteins. Ideally, acetyl-CoA should help initiate appropriate responses to differing levels of energy. Unfortunately, excess calorie intake can lead

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to excess acetyl-CoA, leading to inappropriate acetyl-CoA messages being sent to mitochondria, DNA and proteins. Frustratingly, this can result in low energy and increased inflammation.

Protein acetylation Acetyl-CoA alters the behaviour of many proteins by adding the acetyl part of acetyl-CoA to the protein, in a process known as acetylation. Acetylation is a form of post-translational protein modification, meaning that a protein has had its behaviour altered after its initial gene expression. Little tricks like acetylation, methylation and phosphorylation can give a protein many more uses and will save the DNA the need to have more genes than necessary. Post-translational modification is a bit like a bus and its new route assignment. Imagine a No. 60 bus becoming a No. 75 bus. Like the protein, it’s the same bus, just with a change of route number (like acetylation), giving it a completely different journey.

Acetylation: the addition of the acetyl part of acetyl-CoA to a protein, which alters the protein’s behaviour.

Excess protein acetylation is detrimental to mitochondrial function and is heavily implicated in conditions such as type 2 diabetes, metabolic syndrome, cancer, hearing loss and heart disease (Wagner & Payne 2013). Fasting and calorie restriction can increase mitochondrial protein acetylation. (This is due to an increased dependence on mitochondrial β-oxidation breaking down fatty acids into large numbers of acetyl‑CoA chunks.) But fasting and calorie restriction do not cause the typical problems associated with such excessive acetylation because these lifestyle practices also increase the activity of SIRT enzymes, the anti‑ageing proteins. SIRT enzymes remove acetyl groups from various acetylated proteins (SIRT enzymes are known as de-acetylases).

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Excess acetylation is very ageing. Excess calorie intake increases acetylation to excess without the concommitant increase in SIRT de‑acetylasing activity. In another neat little trick, the anti-ageing SIRT enzymes can only really work when energy levels drop in the cell and mitochondria. SIRT depends on low-energy nicotinamide adenine dinucleotide (oxidized) (NAD+) and cannot use high-energy nicotinamide adenine dinucleotide (reduced) (NADH) (recall that electrons from food convert NAD+ to NADH) (Wagner & Payne 2013). The body needs to experience low energy before it can access more energy and re-activate SIRT, the anti-ageing fountain of youth enzyme. The irony is that, unless we voluntarily reduce our energy, through diet or exercise, we will be forced into chronic low energy through mitochondrial dysfunction.

PGC1-α, mitochondrial biogenesis and acetylation PGC1-α (peroxisome proliferator-activated receptor-γ coactivator) is a protein that is required for mitochondrial biogenesis – that’s the process that synthesizes brand-new mitochondria. High cellular acetyl‑CoA or nutrient excess can lead to acetylation and inactivation of PGC1-α, resulting in a reduction of mitochondrial biogenesis – in other words, why make more mitochondria when there’s plenty of energy to go round? Exercise and calorie restriction can help increase the expression of PGC1-α, in part by increasing deacetylation, or the removal of the acetyl group. Exercise and calorie restriction take off the acetyl group via SIRT1, one of the anti-ageing SIRT family of enzymes. Remember from above that the SIRT enzymes require increases in low-energy NAD+ which exercise and calorie restriction provide. This permits another neat trick that allows low cellular energy to activate PGC1-α and make more mitochondria. Hey presto! Exercise has lowered energy and the cell is able to respond by making more mitochondria. From this point of view, it can be said that athletes in training are actively building an ample supply of mitochondria for their big sporting event.

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Once activated, PGC1-α can also increase the expression of another anti-ageing member of the SIRT family, mitochondrial SIRT3. Many proteins within mitochondria can be acetylated and deactivated by calorie or acetyl-CoA excess, potentially leading to many conditions of ill-health. But if SIRT3 is active in mitochondria, it can combat the effect of such energy excess. Low cellular energy

Over-nutrition

Low cellular energy

Exercise, intermittent fasting

Typical Western diet

Exercise, intermittent fasting

STOP

AMPK

Phosphorylation

PGC1-α

Deacetylation

Increased AMP to ATP ratio

SIRT1

Increased NAD+ to NADH ratio

Mitochondrial biogenesis Figure 6.1 PGC1-α, mitochondrial biogenesis and acetylation

The removal of an acetyl group from PGC-1α by SIRT1 (along with phosphorylation by AMPK (AMP-activated protein kinase) allows for activation of PGC-1α. Once activated, PGC-1α is able to trigger the gene expression required for mitochondrial biogenesis. However, excess acetyl-CoA from excess calorie intake can block the generation of new mitochondria.

The electron transport chain, mitochondrial superoxide dismutase, glutathione (an antioxidant), β-oxidation and ketone body formation can all be compromised by excess acetylation (Giralt et al. 2012). Mitochondria can grind to a halt without enough SIRT3 to keep pulling acetyl groups (derived from acetyl-CoA) away from proteins. For mitochondria, too much acetyl-CoA is too much of a good thing!

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Cytokine: a protein secreted by immune cells which allow cells to communicate with each other. Cytokines can be both pro- and anti‑inflammatory.

SIRT3 expression has been found to be considerably decreased in the pancreatic islets of type 2 diabetes patients. In studies, inhibition of SIRT3 reduces insulin secretion and increases reactive oxygen species  (ROS), inflammatory cytokines and β-cell apoptosis (Caton et al. 2013).

α-Lipoic acid α-Lipoic acid is an absolutely essential nutrient for the activity of the PDC (pyruvate dehydrogenase complex) and energy production in mitochondria. α-Lipoic acid also helps to support mitochondria against the negative effects of excess acetylation associated with type 2 diabetes and metabolic syndrome. Reported mitochondrial benefits of α-lipoic acid include: • • • • • • • • •

prevention of liver triglyceride build-up reduction in liver hydrogen peroxide increase in mitochondrial superoxide dismutase increase in glutathione peroxidase and glutathione reduction in mitochondrial DNA damage activation of the anti-ageing deacetylases SIRT1 and SIRT3 reduction in lipid peroxides such as malondialdehyde support for mitochondrial biogenesis protection against the damaging effects of a high-fat diet. (Valdecantos et al. 2012)

Alcohol, the scourge of mitochondria Alcohol is metabolized to acetate and acetyl-CoA. Worryingly, it has been shown that blood acetate levels can increase 20–30-fold after 71

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an alcoholic drink (Giralt et al. 2012). This acetate load can provide an enormous challenge to cells and mitochondria, with a high degree of protein acetylation. Furthermore, acetaldehyde is formed during the metabolism of alcohol to acetate, and is extremely toxic to the electron transport chain (Manzo-Avalos & Saavedra-Molina 2010). As well as acetyl-CoA overload, alcohol consumes large amounts of NAD+ in dehydrogenase enzymes, which are required for alcohol detoxification. Alcohol is first metabolized to acetaldehyde by losing a hydrogen ion, and NAD+ picks up the hydrogen to make NADH. In the second step, acetaldehyde is metabolized to acetate by losing another hydrogen ion – again NAD+ picks up the hydrogen to make NADH. Therefore, alcohol consumption means that NADH levels rocket up and NAD+ levels fall through the floor! Anti-ageing SIRT enzymes will struggle to function without sufficient NAD+. In a troubling doublewhammy, SIRT enzymes will not be able to undo the damage caused by excess acetate and acetyl-CoA, and mitochondrial dysfunction ensues. As an activator of SIRT1, the polyphenol resveratrol contained in red wine (Cao et al. 2015) may ameliorate some of the negative aspects of alcohol consumption. It’s unlikely that resveratrol is going to undo all the harm caused by alcohol, and so drinking only in moderation (or abstaining completely) is still strongly advised to protect our valuable mitochondria.

Key points for practitioners Acetyl-CoA is much more than just an energy source. In addition to providing a supply of energy to mitochondria, acetyl-CoA can bind to  mitochondrial, nuclear and cellular proteins, altering the behaviour of these proteins. Excessive acetylation of proteins can be inflammatory and ageing. The anti-ageing SIRT proteins help prevent ageing by removing acetyl groups from protein. SIRT proteins are called ‘deacetylases’ because of this action. When looking to support the healthy activity of acetyl-CoA, think resveratrol, curcumin, green tea, α-lipoic acid, the Mediterranean diet, omega-3 fatty acids, exercise and calorie restriction, and avoid excessive alcohol intake. 72

7 Synthesizing Cellular Components

The terms ‘catabolic’ and ‘anabolic’ are freely used without much consideration of what they actually mean in terms of our metabolism and mitochondria. ‘Cata’, as a prefix, means downward and is seen in words such as cathode, catabolic and cataclysm. ‘Ana’, as a prefix, means upward and is seen in words such as anode, anabolic and anatomy. So catabolism is downward metabolism (breaking down and energy production) and anabolism is upward metabolism (building up, growth and proliferation).

Catabolism: breaking down molecules into smaller units to produce cellular energy. Anabolism: constructing molecules from smaller units in the cell.

Mitochondria are at the heart of the decision as to whether a cell will be catabolic or anabolic. Should mitochondria help initiate the breaking down or burning of fuel? Or should they help initiate building

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up cells, through growth and proliferation (remember, proliferation = pro-life-ration)? Ironically, excess pro-life-ration can lead to cancer. In a healthy body, all cells ought to behave unselfishly and holistically, with the whole body in mind. Healthy cells limit their individual growth and undergo apoptosis. Tumour cells become immortalized and have uncontrolled growth. Ideally catabolism and anabolism within the body should be in balance, providing appropriate catabolism for energy and anabolism for growth, repair and inflammation. Excess catabolism is seen in wasting diseases such as type 1 diabetes and the wasting condition cachexia. Excess anabolism is seen in obesity, type 2 diabetes, inflammation and cancer. The typical Western diet leads to excessive anabolism, the cause of the majority of chronic diseases seen in Western society.

Morphing mitochondria to suit cellular needs Embedded within the fabric of a cell is its own evolution from anaerobic archaea and aerobic α-proteobacteria. This means that the cell has the memory to be both anaerobic and aerobic, depending on context and circumstance. Morphing the behaviour of the cell and mitochondria, in response to environmental changes, is all in a day’s work for our cells – and it’s more correctly known as a change of phenotype. In times of low oxygen it is essential, for the survival of a cell, to switch to anaerobic respiration by relying on glycolysis. The cell has an ingenious sensor for low oxygen, called HIF (hypoxia inducible factor). HIF is continually degraded by an oxygen-dependent enzyme when oxygen is plentiful. However, when cell oxygen is at a low level, HIF can no longer be degraded and is able to switch on genes that enable a cell to rely on glycolysis for energy, not the mitochondria. This is called the glycolytic switch. However, it’s not just low oxygen that enables the glycolytic switch.

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Aerobic glycolysis – the essential step to inflammation and proliferation Now this is the interesting bit – cells prefer and need to work anaerobically to grow and proliferate. They need to employ glycolysis – even in the presence of ample oxygen. This is known as aerobic glycolysis. Otto Warburg discovered, in the early part of the last century, that cancer cells used aerobic glycolysis for their metabolism. This observation became known as the Warburg effect (see Chapter 3, ‘Energy Production’, and Figure 7.1). As we shall see, many other health conditions are associated with aerobic glycolysis. More recently, we have started to appreciate that another switch in metabolism has to occur in parallel with the glycolytic switch – this is the lipogenic switch. The lipogenic switch changes mitochondria from adenosine triphosphate (ATP) provider to a supplier of the raw materials needed for cells to grow rapidly. The mitochondrial anabolic transformation is a bit like your local power station morphing into a builder’s merchant. The mitochondrial builder’s merchant supplies us with the building blocks and materials for the fats, cholesterol and phospholipids to help build cell membranes and organelles. The glycolytic and lipogenic switches enable the metabolism to shift toward being anabolic for building, not burning.

Phospholipids: a group of lipids comprising two fatty acids, a phosphate group and glycerol. Phospholipids are important components of all cell membranes.

THE GLYCOLYTIC AND LIPOGENIC SWITCHES The glycolytic switch The glycolytic switch is a shift toward dependence on glycolysis for cellular ATP production. The glycolytic switch can occur when there is insufficient cellular oxygen to allow for oxidative phosphorylation in mitochondria. The glycolytic switch can also occur in the presence of oxygen and is known as aerobic glycolysis or the Warburg effect. The glycolytic switch allows mitochondria to switch 75

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from energy production to being a provider of the raw materials for cellular biosynthesis and proliferation. The lipogenic switch The lipogenic switch occurs in tandem with the glycolytic switch. The lipogenic switch leads to the export of citrate from mitochondria where it is converted to acetyl-CoA, saturated fatty acids and cholesterol. During growth and proliferation, the lipogenic switch helps to provide the lipids required for cell membrane synthesis.

The major errant cause of the shift in the mitochondria to lipid synthesis (the lipogenic switch) is the Western diet, high in sugar and fat (Young & Anderson 2008). The terrible trio of high fat, high sugar and high insulin set a cascade of gene expression in place to enable the lipogenic switch. This gene expression initiates changes in mitochondria to export citrate/acetyl-CoA for biosynthesis, rather than burning. Inflammation, lack of exercise and low omega-3 PUFA (polyunsaturated fatty acid) intake can be other triggers for the lipogenic switch. Remember, if the lipogenic and glycolytic switches are enabled, cells and the metabolism shift toward anabolic metabolism. It’s the morphing of the mitochondria from power station to builder’s merchant that’s at the heart of this profound change. Table 7.1 How diet and lifestyle can support either catabolism or anabolism Catabolism = energy production = reduced inflammation Diet and lifestyle to support catabolism

Effects of an anti-inflammatory diet and lifestyle changes

Dietary polyphenols (resveratrol, EGCG (epigallocatechin-3-gallate), curcumin), omega-3 fatty acids, exercise, reduced calorie intake, Mediterranean diet, fruit and vegetables

Activation of SIRT1 and AMPK (AMP‑activated protein kinase) to trigger mitochondrial biogenesis and increased energy, improvements in gut microbiota, reduced inflammation and anabolism

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Anabolism = biosynthesis = inflammation Diet and lifestyle which supports anabolism

Effects of an inflammatory diet and poor lifestyle

Typical Western diet – high saturated animal fat, sugar, salt, fried foods, low-fibre intake, little or no exercise, excessive calorie intake

Triggering of inflammation, reduced catabolism, low energy, gut microbiota dysbiosis, increased chance of autoimmunity Source: Riccio & Rossano (2015)

The biochemistry of catabolism and anabolism Now it’s time to look at the biochemistry of the shifts between catabolism and anabolism, for those who want a more scientific explanation. The above themes will be repeated, but with more biochemical detail. Acetyl-CoA cannot directly cross from inside mitochondria to the cytosol. To transfer acetyl-CoA out of mitochondria, it first has to be converted to citrate, exported, and then converted back to acetyl-CoA in the cytosol. The export of acetyl-CoA from the mitochondria is required during times of high β-oxidation and high calorie intake, to protect the PDC from being inhibited. Acetyl-CoA export is also needed in times of growth and repair. Effectively, acetyl-CoA export from mitochondria leads to a shift away from burning acetyl-CoA in mitochondria (catabolism) to building outside the mitochondria (anabolism) (Iacobazzi & Infantino 2014). Acetyl-CoA forms the bricks that are the foundation of fatty acids and the cholesterol needed for new cell membrane construction. In addition, acetyl-CoA modifies DNA to support growth and inflammation: the mitochondrial export of acetyl-CoA helps to provide the acetate required to acetylate histones on chromatin, which surround DNA and suppress gene expression. Chromatin is like a large Slinky spring, the toy popular with children. When the chromatin is coiled tightly, gene expression is inhibited; when relaxed, the DNA is exposed and ready for transcription. Acetylation relaxes chromatin and

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results in the expression of genes promoting growth and proliferation (Cai et al. 2011). Inflammatory cytokines and transcription factors act to increase cellular acetyl-CoA by up-regulating the activity of the mitochondrial citrate carrier (CIC). The citrate carrier provides the doorway for acetyl‑CoA to be shuttled from the mitochondria to the cytosol (Pietrocola et al. 2015).

Up-regulation: the increase in activity of a biological system in response to a stimulus.

The raised activity of the citrate carrier in turn leads to the increased generation of inflammatory mediators such as nitric oxide, reactive oxygen species (ROS) and prostaglandins (Infantino et al. 2014). It comes as no surprise that anti-inflammatory omega-3 PUFAs are potent inhibitors of citrate carriers, even in the presence of a high-fat diet (Ferramosca & Zara 2014a). Acetyl-CoA export from mitochondria via the citrate carrier has strong associations with inflammation, proliferation and cancer (Infantino et al. 2014). Moreover, the citrate carrier is highly expressed in cancer cells (Iacobazzi & Infantino 2014). The shift in citrate metabolism from its key role in mitochondrial energy production to its export from mitochondria is a key metabolic switch in cancer. This metabolism-switching effect of the citrate carrier highlights the grave consequences of highly calorific diets. The switch to citrate/acetyl-CoA export during cancer and inflammation adds another piece of the metabolic jigsaw behind tumour cell metabolism. It’s already well known that tumours prefer a lactic-acid environment via increased glycolysis (the Warburg effect). It is less well known that the mitochondria can help drive cancer and inflammation via citrate/acetyl-CoA export. Not only does the lipogenic switch provide lipids for cell membrane construction, but it also allows another clever trick to enable glycolysis to keep running. NADH (an energy carrier for catabolic reactions) and

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NADPH (nicotinamide adenine dinucleotide phosphate (reduced), an energy carrier for anabolic reactions, the ‘P’ signifying the addition of a phosphate group) need to be able to offload their hydrogen ions and electrons, to free up NAD + (nicotinamide adenine dinucleotide (oxidized)) to be able to pick up the next load of energy from glycolysis. In this way the glycolytic and lipogenic switches are interdependent. ATP

Glycolysis

Lactic acid

Pyruvate

The TCA cycle

Palmitate

Fatty acid synthase

Citrate

Acetyl-CoA Cholesterol Lipogenic switch

Figure 7.1 Glycolytic switch: the Warburg effect

The switch from aerobic respiration within mitochondria, to a reliance on anaerobic  respiration, is called the glycolytic switch. This switch is seen in tumour cells and is known as the Warburg effect. The glycolytic switch also allows citrate to be exported from mitochondria for the biosynthesis of saturated fatty acids and cholesterol – known as the lipogenic switch. These two switches turn a mitochondrion from a catabolic (fuel burning) mode to an anabolic (building/biosynthesis) mode.

NAD+/NADH/NADPH are like a hod carrier for ‘energy bricks’. They can only continue to shuttle around energy if they can keep offloading their hydrogen and electron cargo somewhere. This ‘somewhere’ happens to be the electron transport chain during energy-burning catabolism, and into lipids during building-up anabolism. From the above, it can be seen that there is a continuum between excess calorie consumption, insulin resistance, metabolic syndrome, inflammation, excessive growth and, most likely, cancer. Looking after our mitochondria in this context is an absolute necessity.

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8 Ketone Metabolism

There is an exception to the negative aspects of high saturated fat consumption. Strangely, this exception occurs when the ratio of fatty acid to carbohydrate consumption increases rather than deceases. At first glance it seems to be counterintuitive for a troublesome macronutrient to be less of a problem when it is consumed at higher levels. A ketogenic diet (see guidelines in Chapter 16, ‘Diets to Support Mitochondrial Function’) is akin to saying, ‘If you eat fat it will be bad for you – on the other hand, if you eat even more fat, it will be good for you!’ This chapter will discuss both the positive and negative aspects of ketone metabolism. To understand this contradiction, we have to look at the way the liver deals with acetyl-CoA from fat. The liver can only use acetyl-CoA as an energy source if the diet contains carbohydrates. (This is because dietary carbohydrates produce oxaloacetate in mitochondria, which enables the liver to burn acetyl-CoA.) When carbohydrate intake drops, so does mitochondrial oxaloacetate. Now, if fat consumption increases, the liver synthesizes acetyl-CoA that it can’t make use of. The way the liver deals with this excess acetyl-CoA is to package it up into ketone bodies and export these ketones to other organs and tissues.

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Even though ketones are not able to be metabolized within the liver, they are able to be metabolized by the brain, muscles, kidneys and heart. There are three types of ketone bodies: acetoacetate, betahydroxybutyrate (β-OHB) and acetone. Acetone can be cleared through the lungs, and gives a person with high blood ketone levels a characteristic sweet and fruity breath odour. The classic ketogenic diet consists of a ratio of 4:1 long-chain fatty acids (LCFAs)3 to protein and carbohydrate. This high ratio of fatty acids is needed because LCFA metabolism is somewhat inefficient. LCFAs cannot directly enter the bloodstream when eaten and have to be first carried by chylomicrons (lipoprotein particles) through the lymphatic system. Additionally, LCFAs cannot enter directly into mitochondria, needing carnitine to act as a carrier; even then they still require several cycles of β-oxidation to be fully metabolized (Branco et al. 2016). On the other hand, medium-chain triglycerides (MCTs) do not use chylomicrons for absorption or carnitine to enter mitochondria. MCTs can more rapidly enter circulation and therefore create ketones more efficiently. Thus a ketogenic diet using MCTs rather than LCFAs typically only requires an 1.5:1 ratio (or 60% of dietary intake) of fatty acids to protein and carbohydrates (vs the classic 4:1 ratio). Without the high ratio of fats required, the MCT diet is more likely to be adhered to, due to the increased flexibility of food choices (Branco et al. 2016). The type of ketosis that is beneficial for health is called nutritional or dietary ketosis. This is a type of ketosis where blood levels of ketones rise to between 1 and 2 mmol/L after a few days on the diet. Ketone levels can be measured by blood, urine or breath testing. Blood testing is the most accurate, but it can be a little inconvenient for a person to skin prick for each measurement. Urine testing is the most common way for dieters to measure ketones, but it is also the most inaccurate method. Breath testing is becoming more popular and is more accurate than urine testing for assessing ketone levels.

3 LCFA referred to in this chapter represents purely long‑chain saturated fatty acids (not PUFAs and MUFAs).

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Typically, a classic ketogenic diet (4:1 LCFAs to protein and carbohydrate) will consist of 80 per cent fat, 15 per cent protein and  5  per  cent carbohydrate. Whereas if LCFAs are replaced with MCTs, ketosis may be possible on a diet that is only 60 per cent fat (Neal et al. 2009). A ketogenic diet is effectively ended by consuming more carbohydrates, which has the effect of increasing insulin and glucose. This allows the Randle cycle to switch on the pyruvate dehydrogenase complex and use glucose derivatives as fuel. In addition, oxaloacetate can be supplied to the liver from a carbohydrate source. Please see Chapter 5, ‘Maintaining Allostasis’, for more information regarding the switching between carbohydrate and fatty acids as fuel sources. Fasting and exercise are other ways to increase blood ketone levels, particularly if exercising after an overnight fast. Many athletes are moving toward supplementing ketones rather than employing a ketogenic diet as part of their regime. Ketogenic diets may limit training intensity by compromising carbohydrate metabolism, but ketone supplements overcome this limitation (Pinckaers et al. 2017). It is likely that ketone supplements still provide many of the benefits of a ketogenic diet – even when eating carbohydrates. Animal studies have discovered that supplementary ketone esters are able to trigger many anti-ageing, cognitive and physical benefits in a similar way to ketogenic diets (Murray et al. 2016; Veech et al. 2017). If blood levels of ketones become excessive, ketoacidosis (a build‑up of ketones in the body) can occur. Complications with diabetes types  1  and 2 are the most common causes of ketoacidosis, due to the loss of insulin and/or insulin sensitivity. In insulin resistance or diabetes, low cellular insulin means that, even in the presence of high blood glucose, mitochondria will not be able to process acetyl-CoA due to low mitochondrial oxaloacetate and so ketones will continue to rise. Blood levels of ketones over 3mmol/L are considered to put a diabetic patient at risk of ketoacidosis (Dhatariya & Savage 2013). For people with normal insulin secretion, insulin helps to maintain blood ketones at a safe level and so prevent ketoacidosis (Hashim & VanItallie 2014). Considering that (even in healthy people) fasting and a very low carbohydrate intake could raise blood ketones to between 7 and 8mmol/L (Paoli et al. 2015), it is imperative that anyone embarking

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on a ketogenic diet should seek professional supervision and approval first. When considering a ketogenic diet, health conditions such as liver disease, kidney stones, metabolic acidosis, dyslipidaemia and severe cardiomyopathy are all contraindicated (Gupta et al. 2017). Ketoacidosis may be a symptom of diabetes before other symptoms occur, so that some people may not be aware that it may not be suitable for them to follow a ketogenic diet. There is a growing trend toward using ketogenic diets to support patients with both type 1 and type 2 diabetes with many improvements in their overall health condition (Azar et al. 2016; Krebs et al. 2016). However, because of the increased risk of ketoacidosis, it is essential that diabetic patients are supported by a diabetes management team. Drinking coffee has the ability to increase ketones due to the ketogenic effect of caffeine. Caffeine stimulates the release of fatty acids from adipose tissue, raising blood levels of free fatty acids, which then increase ketone formation in the liver (Vandenberghe et al. 2017).

Ketones and disease The brain cannot use fat for energy, but it can use glucose and ketones. In fact in the ageing brain, ketones may even be preferable. In Alzheimer’s disease the brain has difficulty utilizing glucose to maintain energy levels but has no such issue when it comes to ketones (Masino et al. 2016). During fasting, the brain can use ketones for up to 75 per cent of its energy requirement, obtaining the ketones from fatty acids released from their stores in adipose tissue (Dedkova & Blatter 2014). In patients with epilepsy, ketogenic diets have been found to have profoundly beneficial effects for a large proportion of sufferers. Looking at the research, over 30 per cent of epilepsy patients are likely to see a 50 per cent reduction in seizures when consuming a high-fat ketogenic diet. Even more impressive is the fact that almost 10 per cent of epilepsy patients on a ketogenic diet will see a 90 per cent reduction in seizures (Klein et al. 2014). Frustratingly, many epilepsy patients following a ketogenic diet have suffered from a variety of side effects. Diarrhoea, constipation,

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kidney stones, nausea, hyperlipidaemia, vomiting, acidosis, gout, low magnesium and calcium, lethargy, cardiomyopathy (disease of the heart muscle), weight loss and reduced bone density are some of the many side effects that have been associated with the diet (Branco et al. 2016; Klein et al. 2014). It is suggested that minerals are supplemented to compensate for lower absorption, fluid intake increased to ease constipation, and MCT/LCFA balance adjusted to relieve gastrointestinal problems. Many commentators also suggest supplemental fibre (linseed, chia, flax, etc.), especially regarding the microbiome. It is usually recommended to come off the ketogenic diet after two to three months by gradually reducing the fat ratio of the diet (Gupta et al. 2017). Ketogenic diets will not be for everyone and, once again, must not be entered into without prior knowledge of the pros and cons of the diet. Professional supervision is essential. Ketogenic diets can help reverse diabetes-induced kidney disease (Poplawski et al. 2011), and can help protect against cardiovascular disease. Some researchers have found negative associations between a ketogenic diet and cardiovascular health, but this may be due to a pre-existing shift toward ketoacidosis seen in heart failure (Dedkova & Blatter 2014). Once again, because of the increased risk of ketoacidosis, it is essential that a diabetic patient is supported by a diabetes management team. Ketones have been studied extensively as a protective dietary intervention in many cancers. As mentioned in previous chapters, tumour cells gain their energy almost exclusively through aerobic glycolysis. Ketones bypass glycolysis and can only be metabolized in mitochondria via oxidative phosphorylation – to the detriment of glycolysis and, by association, tumour cells (Branco et al. 2016). Mitochondrial biogenesis is increased for a person on a ketogenic diet, along with improvements in glutathione status and oxygen efficiency (Dedkova & Blatter 2014). Many of the benefits of a ketogenic diet for epilepsy patients may be related to improvements in mitochondrial function. People with epilepsy have been found to have many deficiencies in mitochondrial function (Branco et al. 2016; Kim et al. 2015). Ketones can help maintain mitochondrial adenosine

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triphosphate (ATP) despite underlying mitochondrial dysfunction (Frey et al. 2017). In summary, ketogenic diets can be of tremendous benefit to many patients suffering from a wide variety of chronic health conditions. This is because of the profound benefits of ketogenesis on mitochondrial biogenesis and mitophagy. Weighed against these benefits are the short-term and long-term adverse effects. Once again, it is essential for individuals to work with an expert practitioner when embarking on a ketogenic diet, due to the risk of unforeseen adverse effects from the diet.

Key points for practitioners When confronted with very high dietary fat intake (typically 85% of intake for the classical ketogenic diet), liver mitochondria are no longer able to metabolize fat. Liver mitochondria deal with this excess by packaging acetyl-CoA as ketones and then exporting them into the blood, where they can be utilized by other tissue. Ketogenic diets can be supportive for neurodegenerative diseases, epilepsy and some cancers. To support a ketogenic diet, think meat, fatty fish, coconut and olive oil, butter, cream, lard, full-fat milk, eggs, MCT oil, cocoa butter and nuts. Also take care to pay attention to potential side effects.

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9 Altering Immune Function

Mitochondria are heavily involved in the immune system’s strategies for fighting pathogens. Immune cells have to produce both intracellular adenosine triphosphate (ATP) for their own energy, and extracellular ATP, which acts as signals to other immune cells. Mitochondria are also important in generating reactive oxygen species (ROS).

T cells – from an average Joe to superhero! When T lymphocytes or T cells leave the thymus gland they are in the resting or naïve state. Calling T cells naïve implies that they are not working particularly hard, but the naïve label is definitely a misnomer. Naïve T cells are actually on immune surveillance duties and are ready to leap into action and transform into active effector T cells, should they encounter an antigen (a toxin or other foreign substance that stimulates the immune system). This is really like the transformation of an average ‘Joe Public’ to superhero! Mitochondria are at the heart of the transition needed for the transformation of T cells from naïve to effector T cells. Naïve T cells

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engaged in immune surveillance rely on oxidative phosphorylation for their energy, coming from glucose, amino acids and fatty acids being transformed into ATP via the tricarboxylic acid (TCA) cycle and the electron transport chain.

T cell: a leukocyte (white blood cell) that is important in cellmediated, adaptive immunity. Effector T cell: a T cell that organizes the clearance of pathogens and damaged tissue. Excessive effector T cell activity can further damage tissue, leading to chronic inflammation.

In preparing for battle, naïve T cells differentiate to effector T cells such as the T helper cells Th1, Th2 and Th17. These T helper cells proliferate so rapidly that oxidative phosphorylation cannot provide them with sufficient ATP – they need a different armoury to prepare themselves for the fight ahead. So, effector T cells shift toward dependency on glycolysis, which produces ATP at a faster rate. At the same time, their mitochondria switch from ATP producers to fatty acid producers, to assist in the rapid construction of cell membranes for the proliferating T cells. This process is known as a glycolytic switch and lipogenic switch, and occurs in rapidly proliferating cells, including cancer. Because the switch to glycolysis takes place even with a plentiful supply of oxygen, this type of glycolysis is called ‘aerobic glycolysis’. Tumour cells rely on aerobic glycolysis for their metabolism, but this is better known as the ‘Warburg effect’ (Heiden et al. 2009). Out of interest, one of the ways the  ketogenic diet is thought to protect against cancer is via the suppression of aerobic glycolysis (Poff et al. 2017). Just like Hollywood superheroes, you can also be overwhelmed by too many effector T cells running amok and causing chaos. In the right context effector T cells are essential in the fight against antigens, but in excess, they can trigger chronic inflammation and autoimmune disease. T regulatory (Treg) cells are needed to counter the excesses of the effector T cells, and, along with memory cells, they depend mainly on

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the oxidation of lipids via oxidative phosphorylation (MacIver et al. 2013). As shown in Table 9.1, the different types of T cells have different fuel and nutrient requirements. Table 9.1 Fuel requirements of T cells T cell

Metabolism

Immune action

Dietary risers

Naïve

Oxidative phosphorylation/ β-oxidation

Immune surveillance

Balanced diet including protein

Th1

Aerobic glycolysis

Cell-mediated immunity

Th17

Aerobic glycolysis

Mucosal immunity

Carbohydrates, long-chain saturated fatty acids

Th2

Aerobic glycolysis

Humoral immunity

Carbohydrates

Treg

β-Oxidation

Regulate Th1, Th2 and Th17 cells

Memory

β-Oxidation

Immune memory

Carnitine, B2, fatty acids in diet (particulary shortchain saturated fatty acids)

Source: MacIver et al. (2013); Haghikia et al. (2015)

Modifying the immune system using diet and mitochondria If T cell metabolic requirements are different for each variety of T cell expression, then, surely, manipulation of diet and mitochondria could help balance the immune system? Well, the answer is – absolutely! Nowhere has this manipulation of T cell expression by diet been more successful than with multiple sclerosis. Multiple sclerosis is seen as a T cell-mediated disease, where imbalances of effector T cell expression can lead to autoimmunity (Fletcher et al. 2010). The end result of these imbalances is to degrade and destroy the myelin sheath, the fatty layer which surrounds nerves in the central nervous system. 88

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The Swank diet is a low saturated fatty acid diet for helping to cope with multiple sclerosis (MS), which has a long and highly successful track record. Note the diet is not a low-fat diet per se, as it includes moderate amounts of PUFAs and MUFAs. Saturated fatty acids have been shown to increase inflammation via activation of the transcription factor NF-kappaB (Hommelberg et al. 2008) and inflammatory immune receptors (Caesar et al. 2015). Furthermore, in animal and human T cells, long-chain saturated fatty acids have been observed to encourage the polarization of T cells to an autoimmune Th17 subtype within the central nervous system (Haghikia et al. 2015). Please see Chapter 16, ‘Diets to Support Mitochondrial Function’, for further information on the Swank diet. In this chapter, the way that dietary fat influences mitochondria of patients with multiple sclerosis is explored. People undertaking a ketogenic diet have been found to exhibit improved blood lipid profiles (Sharman et al. 2002), even when ingesting high levels of dietary fat. Therefore, they are likely to be largely protected from the inflammatory effects of long-chain saturated fatty acids. However, this protection may not extend to the inflammatory changes seen in intestinal T cell polarization (Haghikia et al. 2015) and toll-like receptors (Caesar et al. 2015).

Antagonist: a substance that opposes or inhibits another substance or process.

An increase in anti-inflammatory T regulatory cells is supported when a diet low in inflammatory mediators effectively reduces NF-kappaB activation of autoreactive Th17 T cells (Park et al. 2014). Remember that NF-kappaB activation leads to citrate/acetyl-CoA being exported from mitochondria to drive fatty acid synthesis (see Chapter 7, ‘Synthesizing Cellular Components’) – which can then feed autoreactive T cells (Berod et al. 2014). What is certain is that PUFAs (such as DHA – docosahexanoic acid – and EPA – eicosapentaenoic acid) can help block the lipogenic

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switch and, in so doing, can help inhibit the initiation of autoreactive T cells and autoimmunity (Berod et al. 2014; Dentin et al. 2005). Interestingly, dietary long-chain fatty acids4 can drive autoimmune reactions in the small intestine (Haghikia et al. 2005). Long-chain fatty acids (LCFAs) are advocated in ketogenic diets, but it might be wise to limit their intake. This is due to saturated fatty acids (such as palmitate) being able to polarize T cells to Th17 and Th1 subtypes (Haghikia et al. 2015). If tolerated, medium-chain triglycerides (MCTs) and short-chain fatty acids (SCFAs) are considered less inflammatory. Lauric acid is often classed as an MCT but still has inflammatory activity and has been linked to the up-regulation of autoreactive Th17 T cells (Bhutia & Ganapathy 2015). Coconut oil contains around 50 per cent lauric acid. On the other hand, SCFAs (from commensal gut microbes feeding on dietary fibre or also found in butter and ghee) can increase T regulatory cell populations and therefore help protect against autoimmunity (Haghikia et al. 2015). It’s not just saturated fat that drives autoimmunity. The Western diet, with its consumption of high levels of simple carbohydrate and saturated fat, is associated with all kinds of autoimmunity, not just multiple sclerosis (Manzel et al. 2014). The influence of diet on T cell expression, and all chronic disease, deserves far more investigation. Another possible way that excess saturated fat and simple carbohydrate consumption may influence autoimmunity is through leptin, a type of adipokine. Leptin is mainly known as a regulator of appetite (acting through the hypothalamus), but T regulatory cells are also sensitive to leptin. Increased circulating leptin, through saturated fat and simple carbohydrate consumption, can suppress T regulatory cells and shift the T cell phenotype toward autoimmune Th17 expression, leading to an increased risk of autoimmune diseases (Correale et al. 2014; Procaccini et al. 2015).

4 LCFA referred to in this chapter represents purely long-chain saturated fatty acids (not PUFAs and MUFAs).

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Adipokine: a type of fat (adipose tissue)-derived hormone. Leptin: a type of adipokine involved in the control of appetite.

There is an exception to the negative side of saturated fat – when it is used as part of a ketogenic diet. The ketogenic diet seems to be entirely contradictory and its effects have been explored in Chapter 8, ‘Ketone Metabolism’.

The subtle effects of the lipogenic switch – lipid rafts A stunning fact about the ingenuity of life is the way that so many subtle processes fall perfectly into place. We already know that the lipogenic switch in mitochondria provides the saturated fat to fuel autoreactive T cells, inflammation and excessive cellular proliferation. We have also learnt that this up-regulated synthesis of saturated fat uses up high‑energy electrons which would normally be destined for the electron transport chain. By continuously taking up electrons, saturated fat synthesis allows glycolysis to continue to make ATP. The body uses fats to make cell membranes and also to make up fatty islands or fatty hubs of activity. Many enzymes and proteins do not freely float around in a cell, but anchor themselves in fat – and in lipid rafts in particular, which are a type of fatty island. The way enzymes anchor themselves to lipid rafts is to take a molecule of saturated fat and bind it to the amino acid cysteine. The most well-known example of this is when the saturated fat palmitate binds to cysteine in a process called palmitoylation. Now, with a palmitate anchor, an enzyme or protein can bed its anchor into a lipid raft and get down to business! Such enzymes and proteins include toll-like receptors (Chesarino et al. 2014), T and B cell receptors (Yount et al. 2013) and endothelial nitric oxide synthase (eNOS – needed to dilate blood vessels) (Resh 1999). Although palmitoylation is an essential process, too much saturated fat may speed up the enzymes excessively. For example, the lipogenic switch may lead to increased

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palmitoylation in prostate cancer, leading to the overexpression of β-catenin (Fiorentino et al. 2008). β-catenin is a protein found to be associated with the invasiveness and proliferation of prostate cancer cells (Jiang et al. 2007). Blocking the lipogenic switch, by inhibiting palmitate synthesis, has been shown to limit prostate cancer cell proliferation and metastasis (Wright et al. 2016). Excess palmitate in the lipid raft can also be problematic. For example, lipid rafts in the frontal cortex of Parkinson’s disease patients have been found to contain excess saturated fat (such as palmitate) and display reductions in omega-3 polyunsaturated fatty acids (Fabelo et al. 2011). Lipid rafts play vital roles in the immune system where they help pick up signals from other immune cells. In the adaptive immune system, T cells and B cells (B cells are leukocytes that secrete antibodies) employ lipid rafts, and in the innate immune system there can be an over-reaction to bacteria if the lipid rafts contain too much saturated fat (Huang et al. 2012; Simons & Toomre 2000). Excess mitochondrial generated saturated fat (lipogenic switch) may also lead to increased allergies. Immunoglobulin IgE (antibodies produced by the immune system) is related to the allergic response and is up-regulated when immune system lipid rafts are dysregulated (Simons & Toomre 2000). Omega-3 fatty acids such as DHA may lessen immune system over-reactivity and allergy by altering the fatty acid content of lipid rafts (Siddiqui et al. 2007). The effect of DHA is like scrambling the immune system’s excessive chatter to calm down inflammation and allergy.

Mitochondrial ATP outside the cell for the ‘immune synapse’ Mitochondria are involved in providing high levels of extracellular ATP for immune cell activation. ATP contains adenosine (one of a category of building blocks for DNA and substances that can be broken down to form uric acid, called purines) which forms an important part of immune system communication. Even though effector T cells may be

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relying on glycolysis for intracellular ATP, it is still mitochondria which provide ATP for extracellular (purine) signalling. Like the nervous system, immune cells have synapses. The immune synapse is the space between immune system cells across which travel exported mitochondrial ATP and its metabolites (purines), so as to communicate with other lymphocytes. Purine receptors are activated at the immune synapse when immune cells are exposed to an antigen (Ledderose et al. 2014). Extracellular ATP (derived from mitochondria) provides signals to purine receptors to help regulate T cell responses (Ledderose et al. 2014).

Immune synapse: a synapse that allows exported mitochondrial ATP and its metabolites (purines) to communicate with other lymphocytes.

Out of interest, extracellular purines, such as adenosine from ATP, also interact with the nervous system and are linked with our sensitivity to pain. This highlights the network of extracellular purine signalling in the immune system and nervous system – both dependent on mitochondrial ATP. It is unsurprising that nerve mitochondrial dysfunction has been found in studies investigating neuropathic pain (Chen et al. 2014). Pancreatic β-cells use extracellular purines to help regulate insulin production. Mitochondrial ATP is exported alongside insulin to help accomplish an extra level of insulin regulation (Tengholm 2014). Incredibly, stimulation of immune T cells by an antigen can double extracellular mitochondrial ATP output in under 30 seconds. The huge increase in ATP output results in the rapid accumulation of mitochondria around the immune synapse (Ledderose et al. 2014). This places mitochondria right at the very heart of an immune response to an antigen. Mitochondrial ATP and purine derivatives help to promote some of the changes required to immune cells, so that they can deal with the immune battle ahead. For example, mitochondrial ATP enables the switch of B lymphocytes from naïve B cells to plasma cells that secrete

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the antibodies immunoglobulin A (IgA) and immunoglobulin G (IgG) (Walker et al. 2014). To be able to double their ATP output on demand, mitochondria have to be at the absolute peak of their efficiency. Consequently, mitochondrial dysfunction can lead to an inability to produce sufficient ATP in response to an antigen. With insufficient ATP at the immune synapse, the result is a suppressed T cell response. Patients with sepsis have been observed to have a lower ATP content in their T cells. This ATP deficiency is likely to contribute to the heavy immune suppression that is frequently seen in sepsis (Ledderose et al. 2014). Antigen-presenting cell

T cell receptor

ATP

T cell

Purine receptor

ATP Calcium

T cell activation Figure 9.1 The immune synapse: mitochondrial ATP assists T cell activation

Mitochondrial ATP is required at an immune synapse to prime a T cell for activation. Mitochondrial ATP is exported from the T cell where it triggers a purine receptor to amplify the initial immune response. Without sufficient mitochondrial ATP, an immune response will be blunted.

Mitochondria and innate immunity The innate immune system is the part of the immune system that responds immediately to pathogens by recognizing the generic components of pathogens, rather than the specific species of bacteria.

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A major part of the innate immune system is the inflammasome, a multi-protein inflammatory complex. The inflammasome is activated by diverse compounds such as bacterial cell wall fragments, viral DNA, asbestos, uric acid crystals, silica,5 cholesterol crystals and alum6 (Oleszycka et al. 2016). The inflammasome is dependent on mitochondrial reactive oxygen species (ROS) for its activity. Mitochondrial ROS can provide the signals to initiate innate immunity and also the raw firepower to help destroy invading pathogens. Specialized lymphocytes called phagocytes engulf and destroy bacterial pathogens by creating very high levels of ROS, which are necessary to kill pathogens effectively. Mitochondrial ROS play a supporting and vital role in this process.

Phagocyte: a type of cell that can engulf and destroy pathogens.

To prove just how important mitochondrial ROS are in killing bacteria, researchers have experimented by priming phagocytes with antioxidants. The antioxidants quenched mitochondrial ROS, which led to poor or ineffective bacteria killing by the phagocytes (West et al. 2011a). The sensing of viral ribonucleic acid triggers the production of interferons, which will attack the pathogens via mitochondrial signalling. Interferons are a type of cytokine which modulate an immune response, and are involved in fighting viruses and attacking tumour cells. During viral infections a protein called the mitochondrial antiviralsignalling protein (MAVS) locates itself in the mitochondrial  outer membrane, signalling the activation of transcription factors and antiviral inflammatory cytokines (Tait et al. 2012).

5 The kind of silica which activates the inflammasome is crystalline silica. Quarry workers, sand blasters and stone masons are at high risk of silicosis due to inhaled silica or quartz triggering the inflammasome (Cassel et al. 2008; Sauvé 2015). 6 Alum is an aluminium salt used for many years as a vaccine adjuvant (Franchi & Núñez 2008).

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In addition to fragments of pathogens activating the inflammasome, components of mitochondria can also activate the complex. Mitochondrial DNA (mtDNA) and the mitochondrial phospholipid cardiolipin should always remain inside mitochondria. If mitochondrial dysfunction occurs and a mitochondrion spews out its components, the inflammasome can identify mtDNA and cardiolipin and trigger inflammation (Gurung et al. 2015). TRAF6

Toll-like receptors

ROS Bacteria Phagocyte Figure 9.2 Mitochondrial ROS help provide the raw firepower to fight pathogens

Toll-like receptors (TLRs) of the innate immune system send signals (via TRAF6) to  mitochondria, for their assistance in fighting pathogens. Mitochondria respond to TRAF6 by increasing their output of ROS. TRAF6: tumour necrosis factor receptor-associated factor 6

Outside a mitochondrion, cardiolipin is known as mito-DAMP – a mitochondrial damage-associated molecular pattern recognized by the inflammasome (Chakraborty et al. 2017). It’s almost as if there is a temporary truce between a cell and a mitochondrion – as long as a mitochondrion knows its place. However, if a mitochondrion should step out of line, then its bacterial origins are remembered and the immune system attacks!

Key points for practitioners In a previous chapter, ‘Synthesizing Cellular Components’ (Chapter 7), we saw how mitochondria can switch from ‘fuel burning mode’ (catabolic)

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to ‘building mode’ (anabolic). When T cells of the immune system respond rapidly to a pathogen, they need to dramatically increase their numbers in a short period of time. The T cells call on mitochondria to supply many of their structural components (to increase their numbers) and help mitochondria switch to ‘building mode’. Unfortunately, the typical ‘Western diet’ can unwittingly shift mitochondria into ‘building mode’ and thereby drive unwanted immune responses, such as seen in autoimmune disease and chronic inflammatory conditions. When looking to protect a person from excessive diet-driven inflammation, think the Mediterranean diet, fruit and vegetables, complex carbohydrates, medium-chain triglycerides, resveratrol, EGCG (epigallocatechin-3-gallate), curcumin, omega-3 fatty acids, exercise and reduced calorie intake. All these compounds and activities can go a long way toward inhibiting the glycolytic and lipogenic switches, promoting the polarization of T regulatory cells and supporting lipid rafts. T regulatory cells preferentially derive their energy from the β-oxidation of fatty acids, yet it is still wise to limit saturated fat intake to mainly medium-chain triglycerides. Longer-chain saturated fatty acids (such as palmitate) are associated with inflammation and should be avoided. It is estimated that palmitate accounts for around 60 per cent of all saturated fat intake in the typical Western diet. This high intake is considered to be a major driver for chronic inflammatory disease (Sobocińska et al. 2018). There is much contradictory information regarding the benefit or harm of dietary fatty acid intake. This is largely due to a profound lack of understanding about the different effects of fatty acid saturation and carbon chain length on our immune system. I hope that this chapter has gone a long way toward explaining these apparent contradictions.

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10 Creating Short Bursts of Rapid Energy

Once a mitochondrion has produced a molecule of adenosine triphosphate (ATP), it is often thought that it is only ATP that is exported to the cell. However, in tissue with high energy demands, the protein-derived compound creatine is also needed (as phosphocreatine) to greatly accelerate energy delivery. The brain, retina, heart, muscle and spermatozoa are all highly dependent on creatine to enable rapid energy delivery (Wyss & Kaddurah-Daouk 2000). The name creatine is derived from the Greek word kreas, meaning ‘flesh’ (Wyss & Kaddurah-Daouk 2000). Creatine synthesis depends on the amino acids arginine and glycine, and requires methylation from the methyl donor S-adenosylmethionine. In fact a huge 40 per  cent of all methyl groups produced in the body are consumed in the synthesis of creatine (Joncquel-Chevalier Curt et al. 2015). Due to their role in the methylation cycle, vitamin B12 and folate will therefore play an essential part in helping mitochondrial ATP get to many energy-depleted tissues.

Methylation: the addition of a methyl group (CH3) to a compound.

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The enzyme mitochondrial creatine kinase (Mi-CK) resides in the mitochondrial intermembrane space. Mi-CK allows the transfer of a high-energy phosphate group from ATP to be transferred to creatine, to form phosphocreatine. A pool of phosphocreatine is maintained in muscle to allow high-intensity work to be carried out over several seconds. Creatine kinase enzymes also exist within the cytosol to ‘recharge’ creatine to phosphocreatine (Wyss & Kaddurah-Daouk 2000). ATP CK ADP

ATP

Phosphocreatine CK Creatine

ADP

Figure 10.1 Mitochondria work to maintain a pool of phosphocreatine in the cytosol

CK (creatine kinase) allows for the transfer of a phosphate group from ATP (adenosine triphosphate) to creatine, to form phosphocreatine. Within the cytosol, phosphocreatine can in turn donate a phosphate group to recharge ADP (adenosine diphosphate) to ATP. A pool of phosphocreatine is maintained in tissues which require high-intensity bursts of work.

Key points for practitioners When cells require rapid bursts of energy, mitochondria may not be able to respond quickly enough to the dramatic increase in demand for energy. To assist mitochondria, phosphocreatine helps to supply this rapid short burst of energy. The nervous system, eyes, heart, muscle and sperm all rely on phosphocreatine to supplement their mitochondrial energy. To support phosphocreatine, think methylation, as a huge 40 per cent of all body methyl groups are consumed to manufacture phosphocreatine. Therefore, folic acid, vitamin B12, vitamin B6 and betaine are essential. Additionally, the amino acid arginine is required to synthesize the skeleton of phosphocreatine before it is methylated.

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11 Calcium Storage and Regulation

Calcium is generally associated with the structural integrity of bones and teeth. Other calcium actions, within the cell and within mitochondria, are less often considered. With increasing scientific knowledge of calcium metabolism, it’s now time to pay close attention to calcium’s subtle but far-reaching effects, which are ably assisted by mitochondria. Calcium is known as a ‘second messenger’ within a cell. It acts as a master controller of cell functions in response to external stimuli, such as hormones and neurotransmitters. So the external stimuli are the first messengers, which then pass on signals to inner-cell second messengers such as calcium. As more knowledge accrues, research continues to uncover the ingenuity of calcium’s control of cell function, through these calcium second messages. In a sense, calcium can be seen to be like the conductor of an orchestra. Calcium allows different parts of the cell to be ‘played’ using calcium waves and pulses as well as increases in cellular calcium. Many parts of a cell are highly sensitive to calcium activation (including mitochondria) which therefore allows calcium extensive control of its cellular ‘orchestra’. Countless processes are triggered and controlled by calcium. From the start of life (creation of an embryo) to the end of life

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(apoptosis), calcium signals are needed. Adenosine triphosphate (ATP) synthesis in mitochondria, gene transcription, muscle contractions, the release of hormones and nerve transmission – all of these actions rely on calcium signals (Santulli & Marks 2015).

Calcium wave: a momentary increase in cytosolic calcium succeeded by another momentary increase. The calcium waves formed can be restricted to one cell or occur across many cells simultaneously.

In addition to calcium regulating mitochondria, mitochondria, in turn, act as regulators of calcium. Mitochondria can mop up excessive calcium to limit its activity, or build a ‘mitochondrial barrier’ to isolate  calcium actions to one part of the cell (Patron et al. 2013), to prevent certain calcium-triggered reactions.

Calcium

Figure 11.1 Mitochondria can build a barrier to isolate calcium actions to one part of the cell

Calcium can act like an accelerator pedal, driving mitochondria and the tricarboxylic acid (TCA) cycle harder to increase ATP. Calcium drives three mitochondrial enzymes to increase mitochondrial ATP production: pyruvate dehydrogenase, isocitrate dehydrogenase and oxoglutarate dehydrogenase. 101

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Magnesium is a natural antagonist of calcium and can help to regulate calcium signals. Considering that 58 per cent of UK adults consume less than the RNI (reference nutrition intake) of magnesium each day (Broadley & White 2010), a huge number of people could be setting themselves up for calcium-related health problems. Many heart conditions are linked to calcium and mitochondrial disorders. For example, calcium channel blocker drugs have antihypertensive effects through their reduction of calcium entry into cardiac cells. For calcium to work correctly in a cell, calcium levels mustn’t be too high or too low, and must be kept within tight limits. Mitochondria and the endoplasmic reticulum (a network of tubules within the cell) are the two organelles that maintain this tight regulation by absorbing calcium, in a process called buffering. The buffering of calcium by mitochondria and the endoplasmic reticulum therefore helps to maintain cellular equilibrium, or homeostasis (Celsi et al. 2009). Calcium waves are one of the tools that calcium uses to control functions within a cell. Heart muscle cells (cardiomyocytes) use calcium  waves to enable contraction. Mitochondria are regulators of calcium waves and can help conserve cardiac energy by dampening excessive heart muscle contraction. Taking the orchestra analogy a little further, a cell could also be seen as a musical instrument, with waves of calcium rather than sound waves and music. Calcium channels, calcium stores and mitochondria could all be seen as the valves that play the notes of calcium waves, which, in turn, control or ‘play’ our cells in a healthy rhythm. ATP Calcium

Figure 11.2 Mitochondria and calcium

Mitochondria’s sensitivity to calcium means that they are able to ramp up ATP production in response to cellular need. Calcium is released into a cell when there is work to be done.

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Since mitochondria can increase ATP in response to cellular calcium, it means that mitochondria can match ATP production levels to the required energy levels of the cell (Bootman & Rietdorf 2015). More cellular calcium demands more action within a cell – mitochondria’s sensitivity to calcium means that they are able to ramp up ATP production in response to cellular need.

Mitochondria, nitric oxide and calcium The enzyme nitric oxide synthase is a calcium-activated enzyme and it produces, unsurprisingly, nitric oxide. Nitric oxide is a gasotransmitter (a simple gaseous compound that has a biochemical function), well known for its ability to dilate blood vessels. Out of interest, other gasotransmitters are carbon monoxide and hydrogen sulphide. In the right place, at the right time and in the right amount, nitric oxide is essential. However, excess cellular calcium can lead to increased nitric oxide synthesis, which can in turn impair mitochondrial function. This is because nitric oxide, and its more toxic by-product peroxynitrite, can undermine the activity of the electron transport chain. If the electron transport chain is compromised by nitric oxide or peroxynitrite, this will lead to increased reactive oxygen species (ROS) and lower ATP output (Brookes et al. 2004). The dilation of blood vessels by endothelial nitric oxide synthase (eNOS) is a vital regulator of blood pressure. Nitric oxide can also help to improve sporting performance in athletes by increasing blood flow and supporting muscle performance (Jonvik et al. 2015). Interestingly, dietary nitrates (in beetroot and spinach) can help improve mitochondrial function and trigger mitochondrial biogenesis (Shiva 2013).

Excitotoxicity Calcium is needed to enable mitochondrial ATP production, but if calcium drives too hard it may literally drive a cell to death, through the actions of apoptosis and necrosis. This happens through calcium

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bringing about an excitotoxic reaction within neurons which then overdrives them, leading to their ultimate destruction.

Necrosis: a type of cell death which stimulates an inflammatory response.

Excess calcium within the nervous system, which can lead to excitotoxicity, is associated with a variety of conditions. Some examples are neuronal hyperexcitability, neurodegeneration, epilepsy, seizures and pain (Decuypere et al. 2011b; Oliveira et al. 2014). The excitatory neurotransmitter glutamate acts on NMDA (N-methyl-D-aspartate) receptors to allow calcium to flow in and increase the excitability of the neuron. Excess glutamate-induced excitability caused by extremely high calcium levels is known to negatively impact mitochondria. High calcium levels can push mitochondria beyond their normal capabilities and may lead to neuronal death – this is essentially the process of excitotoxicity. The trigger for glutamate-induced excitotoxicity can be excess glutamate, inflammation (Dong et al. 2017), nitric oxide (Yuste et al. 2015) and amyloid β, the misfolded protein linked to Alzheimer’s disease (Johanssen et al. 2014). Dietary calcium is not related to excitotoxicity, but there are some concerns regarding supplementary calcium being linked to Alzheimer’s disease, for women with a history of stroke (Kern et al. 2016). Excitotoxicity is a major cause of neuronal death in stroke patients (Rama & García 2016). Could it be that stroke may sensitize some women to supplemental calcium? Using the analogy of the orchestra once again, excitotoxicity would be like the conductor getting his or her band to play faster and faster until all rhythm is lost and all the band members collapse on the floor in an exhausted heap! In the very early stages of excitotoxicity, fission-induced fragmentation of mitochondria occurs and is a tell-tale sign that a neuron is under intense stress (Martorell-Riera et al. 2015). This fragmentation leads to small, fragmented and vulnerable mitochondria

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(Marshall et al. 2015), and is accelerated by nitric oxide derived from neuronal nitric oxide synthase, a calcium-dependent enzyme.

EXCITOTOXICITY Glutamate is the main excitatory neurotransmitter of the nervous system. Glutamate activates excitatory neurons via NMDA (N-methyl-D-aspartate) receptors. NMDA receptors allow the entry of calcium into a neuron, which then acts as a stimulus to many enzymes and mitochondria. Excess excitatory stimulus from glutamate can lead to cellular calcium overload and is known as excitotoxicity. During excitotoxicity, mitochondria take up large amounts of calcium to try to protect the cell, but become overwhelmed. Excess mitochondrial calcium leads to the mitochondrial permeability transition pore opening, resulting in the loss of mitochondria and eventually the loss of an entire neuron. Excitotoxicity is implicated in conditions such as neuronal hyperexcitability, neurodegeneration, epilepsy, seizures, depression, pain and autism spectrum disorders.

Mitochondrial permeability transition pore Another excitotoxic effect of calcium is its effect on a mitochondrial channel called the mitochondrial permeability transition pore (mPTP) (Kinnally et al. 2011). The mPTP is like a valve on a pressure cooker. In the case of mitochondria, too much calcium pressure inside leads to the pore opening and then a complete loss of control over what should be inside or outside mitochondria. When the mPTP opens for too long, a mitochondrion will swell up and stop producing ATP, and release a protein called cytochrome c. When set free from mitochondria, cytochrome c initiates the cellular ‘time bomb’ called apoptosis or programmed cell death.

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In its rightful place in the electron transport chain, cytochrome c is a vital component of mitochondrial ATP production. Outside a mitochondrion, free cytochrome c is a sign that all is not well in the mitochondrial world. Free cytochrome c outside mitochondria initiates the death of a cell by enabling apoptosis. Just by moving a fraction of a millimetre from inside a mitochondrion to outside, cytochrome c transforms from a provider of cell life, to a cellular harbinger of doom.

Motility and neurodegeneration Loss of cellular calcium regulation may lead to the failure of mitochondria to reach sections of a cell. We want our mitochondria to have good motility, so that they can reach all parts of all our cells. Mitochondria are not able to navigate a cell under their own steam; they need to be powered by little protein motors which help them deliver ATP to areas of energetic need. The little motors that drive a mitochondrion on its cytoskeletal track are switched off as calcium levels increase. Healthy mitochondria should be able to increase ATP synthesis, and absorb excess cytosolic calcium, to overcome motor inhibition (Decuypere et al. 2011a; Yi et al. 2004). However, in highcalcium environments, unhealthy mitochondria could become trapped like a boat becalmed on the high seas, their mitochondrial motors unable to drive them out of trouble. Calcium has stalled and flooded their engines. As previously mentioned, high cellular calcium can be caused by excitotoxicity or misfolded proteins (Chaudhari et al. 2014) and by the saturated fatty acid palmitate (Egnatchik et al. 2014). Both misfolded proteins and palmitate can cause stress in the endoplasmic reticulum, leading it to release excessive calcium from its stores. These mitochondrial outboard motors are vital to help protect neurons, which ask their mitochondria to take the long arduous trek along their axons to deliver energy. In motor neurone disease (MND), loss of mitochondrial motility along axons has been linked with elevated cellular calcium. MND has also been associated with a mutation to a gene which encodes a protein related to cellular calcium balance (Mórotz et al. 2012).

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Insulin secretion Insulin secretion is dependent on calcium and mitochondria within pancreatic β-cells. Glucose intake results in an increase in ATP synthesis in the β-cells. ATP blocks ATP-sensitive potassium channels (KATP), causing calcium channels to open. The elevation of intracellular calcium in the β-cell then triggers secretion of insulin (Divakaruni et al. 2011).

Calcium channel

t enden m-dep Calciu secretion insulin

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Potassium channel Figure 11.3 Insulin secretion is dependent on calcium and mitochondria within pancreatic β-cells

The endoplasmic reticulum and mitochondria: cellular calcium managers The endoplasmic reticulum (ER) is an organelle that closely associates with mitochondria. The ER is not often talked about, but it’s a hugely important organelle in relation to calcium regulation and mitochondria. Amongst its many roles, the ER is involved in lipid metabolism, protein folding and calcium buffering and signalling. The close association between the two organelles is mediated by a lipid-rich area called the mitochondria-associated ER membrane (MAM) (Raturi & Simmen 2013). Working together as a team, the ER acts as a cellular calcium source and mitochondria are a calcium destination. 107

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The MAM provides an intimate connection between the two organelles (Raturi & Simmen 2013).

Protein folding: a protein folding into a precise three-dimensional shape. Without the correct shape, many proteins have no function. Calcium buffering: the control of cytosolic calcium levels to modulate calcium-dependent processes.

Bearing in mind how important it is to regulate cell calcium in neurons, it’s not surprising that several studies are finding that the MAM is compromised in neurodegenerative disease. The ER and mitochondria need to be communicating through the MAM to safely regulate their calcium content. An important protein in the MAM is α-synuclein. Impairment of α-synuclein can lead to poor calcium transfer to mitochondria, resulting in fragmentation of the organelle (Calì et al. 2012). The misfolding and aggregation of α-synuclein is a signature of Parkinson’s disease. Since the MAM is α-synuclein-dependent, this means that MAM connection between the ER and mitochondria is also compromised in Parkinson’s disease. A compromised MAM sadly means a compromised mitochondrial population. The pathology initiated by impaired MAM function in dopaminergic neurons is known as the ‘MAM hypothesis’ of Parkinson’s disease (Guardia-Laguarta et al. 2015). And it’s not just Parkinson’s disease where the MAM function has been discovered to be problematic. Alzheimer’s disease and insulin resistance are conditions that both display MAM‑related pathology (Schon & Area-Gomez 2010; Tubbs et al. 2014). Calcium itself is not the problem in health conditions such as neurodegeneration, diabetes, heart disease and stroke – the problem is the loss of calcium homeostasis caused by factors that trigger calcium’s actions as a second messenger.

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Magnesium: the natural calcium antagonist Loss of calcium homeostasis is a major cause of dysfunction in mitochondria. Such situations can be caused by excitotoxicity, misfolded proteins and the saturated fatty acid palmitate. As a natural antagonist to calcium, magnesium plays a vital role in helping to keep calcium in check. Sufficient magnesium intake is therefore essential to ensure that a person can support healthy calcium actions in their cells. Worryingly, as stated earlier, it is estimated that 58 per cent of all UK adults have a magnesium intake below the daily RNI (Broadley & White 2010). However, even if a person consumes sufficient magnesium every day, this may not be enough if they regularly drink alcohol. Regular alcohol consumption can result in a 300 per cent increase in urinary magnesium loss (Broadley & White 2010). Of course, many people have a low magnesium intake and regular alcohol consumption!

BENEFITS OF MAGNESIUM IN MAINTAINING CALCIUM HOMEOSTASIS •

Natural calcium antagonist

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Supports the enzyme calcium ATPase

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Regulates insulin secretion

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Helps maintain the mitochondrial membrane potential

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Prevents calcium-related inflammation

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Stabilizes ATP and ATP generation. (Golshani-Hebroni 2016; Jahnen-Dechent & Ketteler 2012; Rayssiguier et al. 2010)

As important as magnesium is as a regulator of calcium, many of the calcium-driven problems cannot be simply addressed by correcting a magnesium deficiency. As seen from above, maintaining cellular calcium homeostasis is highly complex.

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OTHER NUTRIENTS TO ASSIST CALCIUM HOMEOSTASIS BY REDUCING MITOCHONDRIAL AND ER STRESS •

Ascorbate – has been found to be an important mitochondrial antioxidant in animal liver and muscle (Li et al. 2001).

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Mediterranean diet with CoQ10 – supplementing 300mg CoQ10 alongside the Mediterranean diet (15% protein, 47% carbohydrate, 24% MUFA from virgin olive oil, 10% SFA, 4% PUFA) has been shown to result in a reduction in ER stress in elderly men and women (Yubero-Serrano et al. 2012). See Appendix 1.

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Astaxanthin – has been found in a cell-based study to protect mitochondria against oxidative stress (Wolf et al. 2010).

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CoQ10 – CoQ10 metabolites have been found to buffer and support calcium actions in mitochondria (Bogeski et al. 2011).

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Betaine – offers protection against alcohol-induced ER stress in animal livers (Kaplowitz & Ji 2006).

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Lion’s mane mushroom – has been found to decrease ER stress in a cell-based study (Wong et al. 2012). (Bogeski et al. 2011; Kaplowitz & Ji 2006; Li et al. 2001; Wolf et al. 2010; Wong et al. 2012; Yubero-Serrano et al. 2012)

Key points for practitioners Although mainly thought of in relation to bone, calcium plays a vital role in driving many cellular processes, including controlling mitochondrial output. In excess, calcium can over-drive mitochondria, leading to cell death. This is essentially the mechanism for excitotoxicity in many neurological conditions. Excess calcium can be problematic to pancreatic β-cells of the pancreas in type 2 diabetes. Calcium channel antagonists are used for heart disease patients, to support weakened heart muscle from being overwhelmed by calcium. When supporting calcium metabolism, the most important mineral to consider is magnesium. Magnesium is depleted in many people and is one of the most common deficiencies.

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12 Apoptosis Programmed Cell Death

Apoptosis is a type of programmed cell death which acts to preserve the integrity of tissue and organs, and the body as a whole. In cancer, there isn’t enough apoptosis and, in degenerative disease, there is excessive apoptosis. Mitochondria play a central role in the initiation of apoptosis. Cells undergoing apoptosis choose to die (or are chosen to die) because they are excessively damaged or have outlived their useful lifespan. Compared to cell death via necrosis, apoptosis is a ‘clean’ cell death due to the dying cells being engulfed and digested by phagocytes from the immune system. In necrosis, cells die by spewing out their intracellular contents, setting off an inflammatory response due to the immune reactivity of many intracellular components. The mechanism of apoptosis was first described by Kerr et al. in their seminal paper of 1972. In a theme that runs in common with endosymbiosis and mitophagy, the concept of apoptosis highlights the innate intelligence of a living system. The concepts of apoptosis, endosymbiosis and mitophagy have all had to overcome resistance from a narrow-minded acceptance in academia that living systems are of limited intelligence. After all, why would a cell actually choose to die? In a reductionist scientific paradigm it is quite easy to overlook an

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intelligent mechanism (such as apoptosis) because too much focus is placed on individual components of the system, rather than on how the components interact with each other. Apoptosis is initially dependent on a death signal being initiated. This death signal can come from the immune system, chemotherapy drugs, radiotherapy, DNA damage, or other loss of cell function and integrity. Once the death signal is initiated, mitochondria translate the signal and then respond by releasing cytochrome c from the electron transport chain. As we’ve seen, cytochrome c performs a vital role in adenosine triphosphate (ATP) synthesis when embedded in the electron transport chain, but, when released, plays a completely different role. Within the electron transport chain cytochrome c helps give life to the cell – but freed from mitochondria, cytochrome c activates and forms part of the deathly apoptosome assembly (Adrain & Martin 2001). The apoptosome, a body formed when cytochrome c is released from mitochondria, controls the production of cell death proteins called caspases – caspases 3, 7 and 9 all initiate the final step of apoptosis by causing cell shrinkage, DNA fragmentation and cell ‘blebbing’. Cell blebbing is where the internal structure of the cell degrades, leading to protrusions of the cell membrane, which, in turn, leads to the formation of small cell fragments (apoptotic bodies). These fragments are engulfed, digested and recycled by phagocytes of the immune system (Adrain & Martin 2001). In cancer, insufficient apoptosis occurs and tumour cells start to develop an ‘immortalized’ behaviour or phenotype. Inflammation can promote the expression of IAP proteins (inhibitors of apoptosis) which allows continued tumour growth. The polyphenol curcumin acts to suppress IAP and is one of the many ways that this polyphenol helps protect against cancer (Woo et al. 2003). In degenerative disease, there is excessive apoptosis. For example, in Parkinson’s disease, dopamine-producing neurons of the substantia nigra (a structure in the midbrain that is important in reward and movement) undergo apoptosis, resulting in the characteristic tremor of this neurodegenerative disease. In Parkinson’s disease, the apoptosis cell

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death machinery is working all too well, with damaged neurons being cleared without giving any thought to the consequences. One reason for excessive apoptosis in degenerative diseases is the lack of day-to-day mitophagy and active regeneration. Once again, Western diet and lifestyle, combined with high simple carbohydrate and saturated fat intake, can take its toll. High insulin or insulin resistance and low exercise levels can lead to the inhibition of mitophagy and cellular regeneration. Without regeneration, more dysfunctional mitochondria accumulate, leading to excessive reactive oxygen species (ROS) and cell damage. Once a cell is damaged beyond a certain threshold, apoptosis is initiated. Apoptosis is normally essential, but if almost all cells of an organ are dysfunctional, then, sadly, the outcome is degeneration and organ failure. From previous chapters it would be easy to form the impression that oxidative phosphorylation is a good thing, and that excessive glycolysis is bad – particularly if it is aerobic glycolysis (associated with inflammation and cancer). However, in the case of degenerative disease, a reliance on more glycolysis has been found to be protective against excessive apoptosis (Schapira 2009). This goes to show that every body mechanism has its place and is not inherently good or bad. The problem is one of inappropriate body strategies occurring at inappropriate times.

Key points for practitioners Apoptosis, or programmed cell death, is carried out when a cell has outlived its useful life. In degenerative disease, apoptosis occurs excessively, and in cancer there is insufficient apoptosis. Mitochondria play a central role in initiating apoptosis. Interestingly, the polyphenol curcumin can be supportive in both degenerative disease and many cancers. When supplementing curcumin to support neurodegenerative disease it would be wise to choose a fat-soluble formulation to assist the polyphenol’s transition across the blood–brain barrier. Meriva is one of the most studied fat‑soluble formulations of curcumin (Ullah et al. 2017).

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13 Haeme Production

Iron Mitochondria are not often included in discussions on iron metabolism but, importantly, there are two major iron-related processes that occur within this organelle. These are the construction and the use of two iron components: haeme and iron-sulphur clusters. Some researchers even feel that mitochondria may influence whole-body iron absorption to provide the necessary iron for a mitochondrial haeme factory. Mitochondria also have their own ferritin (a protein that stores iron) called mitochondrial ferritin or Ftmt (Richardson et al. 2010).

Haeme Mitochondria begin and end the construction of haeme, the compound at the heart of blood haemoglobin. There are eight steps required to produce haeme; the first and last three occur in mitochondria, the second to fifth occur in the cytosol. The first step in haeme synthesis is

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vitamin B6 dependent. The final step is where another mitochondrial iron-containing enzyme, ferrochelatase, inserts iron to complete the haeme molecule. Lead and aluminium exposure is disastrous for haeme synthesis as both toxic metals can completely block or undermine many of the steps that create haeme, resulting in a chronic haeme deficiency (Flora et al. 2012; Osinska et al. 2004). Haeme deficiency has been found to trigger many of the symptoms and signs of Alzheimer’s disease (Atamna et al. 2002), suggesting that failings in mitochondrial haeme synthesis could be one of the factors driving neurodegenerative disease and premature ageing of the brain. Haeme is most well known as a component of haemoglobin, the protein that transports oxygen in the blood. Haeme is also an important component of the cytochrome enzymes involved in phase 1 liver detoxification, hormone synthesis, vitamin D metabolism and the electron transport chain.

Iron-sulphur clusters Complexes I, II and III of the electron transport chain contain iron-sulphur clusters that help to enable electron transfer within mitochondria. Interestingly, ferrochelatase, the enzyme that inserts iron into haeme, is itself an iron-sulphur cluster-containing enzyme (Atamna et al. 2002). Iron-sulphur clusters also are essential components of tricarboxylic acid (TCA) cycle enzymes and DNA synthesis and repair enzymes (Vaubel & Isaya 2013). Failure to produce functional iron-sulphur clusters can be catastrophic. Nowhere is this more apparent than in Friedreich’s ataxia, a crippling and fatal genetic disease. Symptoms of Friedreich’s ataxia include loss of movement and co-ordination, diabetes, vision and hearing loss, heart disease and muscle weakness. The genetic defect in Friedreich’s ataxia results in low levels of frataxin, a protein that helps to assemble iron-sulphur clusters in mitochondria (Vaubel & Isaya 2013).

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The dark side of iron Friedreich’s ataxia is an extreme example of the importance of mitochondrial iron-sulphur clusters. However, it does illustrate the depth of the impact of mitochondrial iron dysfunction on the body at all levels. Although most genetic diseases are rare, the way the pathology of genetic disease expresses itself can help give us greater insight into related lower-level dysfunction and chronic health issues. Friedreich’s ataxia awakens us to the dark side of iron. Many metals are important in our metabolism due to their inherent instability. It’s their instability that makes them so useful – but only in the right place and the right time. If we fail to harness and control their instability, by not having the proteins in place to bind them, then the harm to our body can be immense. Unbound iron can trigger the Fenton reaction, which results in the production of the highly toxic hydroxyl radical. A large part of Friedreich’s  ataxia pathology is linked to the damage caused by the hydroxyl radical and the resulting oxidative stress (Armstrong et al. 2010). Much of the advice for taking iron supplements often concentrates on increasing iron absorption. It is often suggested that tea should be drunk separately from iron supplementation, to avoid the tannins (the polyphenols in tea) binding iron and decreasing absorption. Now that we are much more aware of iron’s potential harm, should we be drinking more tea to bind any stray iron from inducing oxidative stress? The answer could be ‘yes’ in cases of iron overload since tea tannins are very effective at blocking the damaging effects of iron (Andrade et al. 2006). Iron is essential for life, but mishandle it and it can play a major role in ill-health, degeneration and even cancer (Andrade et al. 2006). I’m not saying never to supplement iron, but that you should supplement wisely, understanding the risks and damage that could be accumulating behind the scenes. Health and safety advisors carry out risk assessments, and there’s a good case for using the same attitude when supplementing iron. I thoroughly recommend reading the paper ‘Iron behaving badly’ by Douglas Kell for anyone who advises on iron supplementation

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(Kell 2009). He outlines how poor iron metabolism can be implicated in or exacerbate many chronic or degenerative diseases. Paradox is not a word that many practitioners want to hear – the fact that some interventions may provide simultaneous benefit and risk. Of course it is important to personalize healthcare – but often only the benefits are considered, and not the risks. True personalization requires the practitioner to have a complete awareness of the benefits and risks of an intervention – beyond standard practice protocols.

Key points for practitioners The production of the haeme molecule starts and ends in mitochondria. Not only is haeme a core component of oxygen-carrying haemoglobin, it also supports the activity of many other enzymes, including liver detoxification enzymes. Although iron is essential for life and iron deficiency anaemia must be supported, iron does have its dark side, particularly as we age. It is wise to be cautious when supplementing iron. For more information regarding iron supplementation, please read the Dietary Supplement Fact Sheet on iron from the US National Institutes of Health: https://ods.od.nih.gov/factsheets/Iron-HealthProfessional

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14 Supporting Kidney Detoxification and Hormone Synthesis

In a similar way to haeme, the synthesis of urea is shared between cytosolic enzymes and mitochondria. Out of the five steps in the urea cycle, two are in mitochondria and three in the cytosol. Synthesis of urea occurs mainly in the liver and to a lesser extent in the kidneys. When protein is broken down (deaminated), ammonia is released. Ammonia is toxic to the body, with the nervous system being particularly sensitive to its effects. In Chapter 8 we saw how the liver’s production of ketones could be of benefit to the nervous system. In the case of ammonia, it’s the removal of ammonia by its conversion to urea in the liver that protects the nervous system. That’s two good reasons to look after your liver and, in doing so, protect your nervous system! Patients with liver cirrhosis can develop psychiatric symptoms due to poor ammonia clearance. This is in part due to dysfunctional liver mitochondria undermining the urea cycle. (The urea cycle converts ammonia into urea.) Ammonia has a direct negative impact on astrocytes (cells closely associated with neuronal synapses) in the brain. Ammonia damages the brain and nervous system indirectly by initiating an inflammatory response via neutrophil activation. Neutrophils are a type of white

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blood cell associated with oxidative stress and inflammation (Shawcross et al. 2010).

Pregnenolone: the mother of steroid hormones Pregnenolone is a steroid that is a precursor to all other steroid hormones – this effectively makes pregnenolone the mother of all steroid hormones. The manufacture of pregnenolone occurs in mitochondria. The first step in pregnenolone production is the import of cholesterol into mitochondria. You will remember that cholesterol synthesis actually starts with the export of citrate from mitochondria (see Chapter 3, ‘Energy Production’). Most cholesterol is synthesized in the liver, although the brain does have its own independent metabolism. Next, cholesterol is converted to pregnenolone by the enzyme CYP11A1, a haeme-containing enzyme assisted by adrenodoxin, an iron‑sulphur cluster enzyme (Strushkevich et al. 2011). Both enzymes are dependent on mitochondrial iron metabolism for their own synthesis. No steroid hormone synthesis can occur if there isn’t a correct balance between the fission and fusion of mitochondria (please see Chapter 4, ‘Mitochondrial Dynamics’, for a refresh on fission and fusion, if needed). Before steroid hormone synthesis can take place in an organ, mitochondria need to be elongated and fused. Researchers have found a direct correlation between the levels of fused mitochondria and progesterone production (Duarte et al. 2012). Insulin resistance is one of the main reasons why mitochondria struggle to fuse correctly. Therefore insulin resistance can have a major impact on steroid hormone synthesis.

Key points for practitioners When protein is broken down, ammonia is released. Ammonia is toxic for much of the body and therefore is converted into urea (as a safety mechanism) with the assistance of liver mitochondria. Urea is then

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flushed out through the kidneys into urine. Liver disease can lead to accumulation of toxic levels of ammonia within the nervous system. To protect against excess ammonia it is important to not consume excessive alcohol, be careful when following a high protein diet and to drink plenty of fluids to assist the kidneys in flushing out urea.

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15 Health, Toxicity and Hormesis

This book’s aim is to move away from the adversarial ‘us against nature’ toward a more integrative approach – it’s the mild toxicity of nature that helps us age healthily and to regenerate our mitochondria. For example, it is reactive oxygen species (ROS) which trigger both mitophagy (to remove damaged mitochondria) and mitochondrial biogenesis (to generate new mitochondria) (Frank et al. 2012; Yoboue & Devin 2012). There are completely justified concerns about the increasing toxicity of our environment, but there is also a need to understand that too little toxicity is just as bad as too much! A major problem is that we have got ourselves into a muddle about what is unhealthy, what is healthy and what is mildly toxic but then healthy.

Health and toxicity Exercise is beneficial because the transient increase in ROS leads to a compensatory action that improves our health. Taking certain supplementary antioxidants during exercise may therefore undermine the beneficial effects of exercise on our health. For example, subjects

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taking part in a study in Germany found that if they took 1000mg of vitamin C and 400IU of vitamin E a day their exercise-induced improvements in insulin sensitivity were negated (Ristow et al. 2009). This discovery flies in the face of our present understanding of ROS as being only damaging to health. Overtraining and excess ROS are damaging, but again, too little ROS are as bad as too much. Radon gas is considered to be a carcinogen, but in reality, our relationship with this ubiquitous radioactive gas is rather more complex. Radon gas exposure is carcinogenic to smokers, but surprisingly, in small doses, it can actually help protect against lung cancer in non‑smokers (Scott 2011). Fruit and vegetables contain pro-oxidant compounds, which lead the antioxidant response element (ARE) of our DNA to activate the gene expression of many endogenous antioxidants. Such compounds include superoxide dismutase (SOD), catalase, glutathione peroxidase and haeme oxygenase (Bhakkiyalakshmi et al. 2015). Therefore the benefit to health from fruit and vegetable intake may be their pro-oxidant activity, in addition to their antioxidant activity (Plauth et al. 2016). Plant compounds ingested in food provide a low level of healthpromoting pro-oxidants. When consumed as concentrated supplements, care has to be taken to avoid potential adverse effects. For example, quercetin can increase superoxide levels in mitochondria (Bouayed & Bohn 2010), and epigallocatechin-3-gallate (EGCG) – from green tea – can trigger the production of hydrogen peroxide (Y. Wei et al. 2016). Sadly, at the time of writing, there are no safe upper limits for these plant compounds (Bouayed & Bohn 2010). Some degree of ROS generated by plant compounds are beneficial due to activation of the ARE. However, the threshold between benefit and harm is likely to be highly individual, with toxicity levels dependent on a person’s ability to mount a hormetic response, their genetics to express endogenous antioxidants, their present toxic load (e.g. are they a smoker?), and how many other compounds they are consuming. However, the vast majority of people consume far too little fruit and vegetables, so their potential toxicity should not be used as an excuse to avoid them! The shearing of water molecules (near waterfalls and breaking waves of the sea) is a common source of negatively charged ions in the air. Negative ions in the air are known for their health-promoting benefits, 122

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but again, their benefit to us is via their mild toxicity. Negative ions trigger an endogenous up-regulation of the enzyme superoxide dismutase, and it’s this reaction which improves our health (English 2013; Kosenko et al. 1997). Therefore, it is the mild toxicity of these environments which provide their health-promoting effects – again by increasing the activity of our own superoxide dismutase (Iwama 2004). At first the seemingly contradictory examples above make no sense, unless we unpick a basic assumption embedded within our beliefs about toxicity: the assumption that there is a linear association between health and toxicity. This means that we are effectively denying the innate intelligence of life throughout evolution. In all living organisms throughout evolution, life turns what at first appears to be a disadvantage into not only an advantage, but a quantum leap in evolution. A prime example of this evolutionary stimulus is oxygen. At first mainly a waste gas from early-photosynthesizing bacteria, the ingenuity of life did far, far more than countering the toxicity of oxygen. For those species that survived, oxygen was the catalyst to drive evolutionary exploration to another level. Oxygen was the stimulus for endosymbiosis, where two organisms united to form the basic cell and mitochondrion of all complex life (eukaryote). However, they didn’t leave it there – they went to use genetic ‘genius’ to edit their genes in a hugely advantageous way. Their gene editing and gene growth formed a genome 200,000 times larger and 5000 times more energetic than their early bacterial counterparts (Lane & Martin 2010). No wonder there was an explosion of complex life-forms after this incredible ‘ingenuity’! What unites all life is its creativity in the face of adversity. There is no ‘blind watchmaker’ here – it is life with its eyes wide open, being fully and actively creative.

Hormesis So if our relationship between health and toxicity is not linear, then what exactly is it? Non-linear is the scientific answer, but it doesn’t really inform us about what’s actually going on. The answer is hormesis – it’s where a little toxicity provides us with improvements in health and protection from ageing. 123

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Excess ROS exposure

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Hormesis Insufficient ROS exposure

Increasing ROS exposure Figure 15.1 Hormesis

Hormesis occurs when a low level of ROS exposure triggers a beneficial healthy and anti-ageing response in the host. The dotted linear curve displays the previous assumption that all ROS are harmful to health.

If exercise, fruit and vegetable compounds, radiation and negative ions were toxic in a linear way, the dotted line on the graph in Figure 15.1 would apply. Any increase in our exposure to them would be harmful. However, they are not harmful at the right level of exposure, due to hormesis. Our reaction to them, via hormesis, means that the ‘J’-shaped curve applies. A little toxicity from our exposure to these mild toxins improves our mitochondria and overall health.

Mitohormesis Mitochondria benefit hugely from hormesis, with mitochondrial hormesis aptly named mitohormesis. Mitochondria exposed to the low-level toxicity of fruit and vegetable compounds are effectively preconditioned to later exposure of even higher levels of ROS. This makes them far more resilient to environmental insults compared to unexposed mitochondria (Biasutto et al. 2011).

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Dietary restriction and exercise can promote mitohormesis by increasing ROS production. This has the effect of activating the processes which allow mitochondrial quality control and regeneration (Tapia 2006). Please read Chapter 4, ‘Mitochondrial Dynamics’, for more information on mitochondrial quality control.

The retrograde response – when mitochondria call for help Normally, communication between the cell nucleus and mitochondria goes from the nucleus to mitochondria – this is called anterograde signalling. When mitochondria are becoming dysfunctional, the signalling reverses, with mitochondria calling out for help from cellular DNA – this is called the retrograde response. Organisms that allow a retrograde response from mitochondria to nucleus are able to extend their lifespan and protect against ageing. The nucleus responds to a mitochondrial ‘cry for help’ by up-regulating genes which help rebuild the tricarboxylic acid (TCA) cycle and electron transport chain, import proteins into mitochondria, and activate mitochondrial biogenesis (Butow & Avadhani 2004; Jazwinski 2013). Glucose has been found to suppress the retrograde response from mitochondria. This suggests that the typical Western diet (high in glucose-rich simple carbohydrates) may make the nucleus deaf to the needs of ailing mitochondria (Jazwinski 2013).

Mitochondrial unfolded protein response Many cell proteins need to be folded before they can function correctly. In the cytosol, there are numerous protective proteins (chaperones) to assist with correct protein folding, and many enzymes to degrade faulty misfolded proteins. The relative isolation of mitochondria from the rest of the cell means that they require their own strategy to deal with misfolded and unfolded proteins. This is called the mitochondrial

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unfolded protein response (UPRmt). As we age there is a need to up‑regulate the UPRmt, as protein-folding stresses generally increase with ageing (Jovaisaite et al. 2014). In a similar way to the retrograde response, the UPRmt is a signal to cellular DNA for help. The protective action from cellular DNA then creates a beneficial outcome for mitochondria. Both resveratrol and the supplement nicotinamide riboside (precursor to nicotinamide adenine dinucleotide (oxidized) (NAD+)) can activate the UPRmt and help extend lifespan in cell-based studies (Jovaisaite et al. 2014). A little toxicity from unfolded or misfolded proteins has a hormetic effect and extends life. In excess, protein misfolding can lead to diseases such as type 2 diabetes, Parkinson’s disease and Alzheimer’s disease; all these diseases have misfolded proteins implicated in their disease pathology. There are many reasons for excess misfolded proteins, including inflammation, oxidative stress, poor cellular protein degradation and free iron. In the case of type 2 diabetes, the misfolding of the pancreatic protein amylin (also known as islet amyloid polypeptide) is due to high glucose consumption (Pillay & Govender 2013).

Toxicity Hormesis can only make use of a limited amount of toxicity to provide health benefits. Beyond hormesis, the full force of the damaging effects of toxicity appear. Toxicity can appear in many guises such as pesticides, metals, hydrocarbons, radiation, stress, inflammation, food processing, poor diet, toxic chemicals and toxic endogenous metabolites. Mitochondria are profoundly affected by toxicity. Stressed mitochondria can no longer undergo quality control through fusion and fission to maintain their integrity. Their mitochondrial DNA become more vulnerable to damage, resulting in poor electron transport chain function. Finally, mitochondria can initiate apoptosis if normal stress-coping strategies fail (Barbour & Turner 2014). Part II of this book will look at how overstressed mitochondria play a role in many health conditions.

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Key points for practitioners Hormesis occurs when a low level of ROS exposure triggers a beneficial healthy and anti-ageing response in the host. Surprisingly, exercise, sea air and fresh fruit and vegetables are beneficial partly because of their mild toxicity (hormesis effect). To support healthy levels of hormesis, be sure to consume plenty of fresh fruit and vegetables, exercise regularly and spend time outdoors (near running water or by the sea if possible).

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Part II The Influence of Mitochondria in Disease In Part II of this book the aim is to pull together the theories and mechanisms explored in Part 1, and apply them to a set of mitochondria-related health conditions. In this way we can see how the mitochondrial mechanisms play out in the body as a whole and how  mitochondrial dysfunction plays a part in many of our most common chronic illnesses. When contemplating diverse health conditions, such as autoimmunity, depression and osteoarthritis, mitochondria are not usually considered as part of the pathology. However, immune system T cells, the brain and bone are all highly dependent on well-functioning mitochondria. Part I informed us that mitochondria are more than just energy factories producing adenosine triphosphate (ATP). They also play a vital role in inflammation and proliferation, and in helping to provide the raw materials for the growth of tissue and immune cells. Mitochondrial-derived fats, cholesterol and proteins are needed to drive inflammation and growth. There is good reason that proliferating cells work anaerobically – mitochondria are needed to provide these building blocks of growth, which, as you will recall, is an anaerobic process, rather than produce ATP, which is an aerobic process. 129

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Mitochondria under excessive stress can initiate apoptosis (programmed cell death). In neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, there is excessive apoptosis of neurons. In cancer, the opposite is true; too little apoptosis leads to tumour growth. Mitochondria are implicated in insulin resistance, a precursor to metabolic syndrome and type 2 diabetes. Insulin resistance is also involved in many other conditions such as cancer, heart disease, osteoarthritis, cholesterol metabolism and autoimmunity. Part II also includes a selection of mitochondria supportive nutrients and diets to consider, with supplement dosage guidance included in Appendix 2. Chapter 17, ‘Laboratory Tests and Biomarkers Related to Mitochondrial Function’, explores the use of laboratory tests to help determine a patient’s mitochondrial health. Many of these tests will be well known to practitioners. However, the information that the tests reveal about mitochondria may be less well known.

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Mitochondria are negatively affected by a diet that is high in carbohydrate and sparse in nutrients. Unfortunately, these attributes are typical of diets in the West. This type of diet is inflammatory and can force mitochondria to ‘switch’ to an anabolic mode found to be increased in diabetes, metabolic syndrome and cancer. The dietary inflammatory index is an index of the inflammatory effects of food created by University of South Carolina epidemiologists James Hébert and Nitin Shivappa. Around 2000 studies on the inflammatory effects of food have been assessed to compile the dietary  inflammatory index. The score arrived at for the most inflammatory diet is +7.98. The score for the most protective anti‑inflammatory diet is –8.87 (Shivappa et al. 2014). Unsurprisingly, the Mediterranean diet (see below) comes out as an anti-inflammatory diet with an index score of –3.98. The typical Western diet comes out with a highly inflammatory index of +4.07 (Steck et al. 2014). The dietary inflammatory index is a good way to see if a person’s diet is driving their mitochondria toward catabolic (energy-producing)

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or anabolic (inflammatory and proliferative) metabolism. Please read Chapter 7, ‘Synthesizing Cellular Components’, for more information. There are some concerns about the index due to the different methodologies used in many of the studies (Wallis 2017). This does mean that the dietary inflammatory index should be used as a useful guide to help reduce inflammatory food intake, rather than treating the index as an accurate measurement of inflammatory food consumption. Following is a discussion of specific diets that are protective of mitochondria. Some help to optimise mitochondrial function generally; others are evidenced only in relation to specific chronic conditions. A free dietary inflammatory index initial screening tool is available for download via Google Play or iTunes. The University of South Carolina has also developed a more comprehensive dietary analysis tool using IF TrackerTM (Bluvas 2015). For a small fee, IF TrackerTM is also available for download via Google Play or iTunes.

The ketogenic diet There is an increasing amount of evidence supporting the use of ketogenic diets to assist in many health conditions – particularly where mitochondrial dysfunction is implicated. Health conditions with strong evidence to support the beneficial effects of a ketogenic diet are: epilepsy, neurodegeneration (Elamin et al. 2017), type 2 diabetes, obesity and heart disease (Azar et al. 2016). Ketones produced when a person undertakes a ketogenic diet have been found to support the mitochondrial electron transport chain (Frey et al. 2017) and mitochondrial biogenesis, and raise nicotinamide adenine dinucleotide (oxidized) (NAD+), the co-enzyme which also acts as a marker for mitochondrial health (Elamin et al. 2017). Please refer to Chapter 8, ‘Ketone Metabolism’, for more in-depth information on the mechanisms behind ketogenic diets. See Feinman et al. (2015) and Masino et al. (2016) for highly informative reviews of ketogenic diets for health issues.

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THE KETOGENIC DIET GUIDELINES The classic ketogenic diet consists of a ratio of 4:1 long-chain fatty acids (LCFAs) to protein and carbohydrate. Typically, a classic ketogenic diet will consist of 80 per cent fat, 15 per cent protein and 5 per cent carbohydrate. Medium-chain triglycerides (MCTs) are absorbed more efficiently than LCFAs and can help achieve ketosis with a diet consisting of 60 per cent MCTs (Neal et al. 2009). Suggested food intake for a ketogenic diet: •

Fat sources: meat, fatty fish, coconut and olive oil, butter, cream, lard, full-fat milk, eggs, MCT oil, cocoa butter and nuts. Coconut oil, full-fat milk, cream, butter and cheese are all sources of MCTs.

•

Protein: meat and fatty fish such as salmon, mackerel and tuna. For meat choose cuts with more fat. For poultry choose darker meat.

•

Vegetables: ››

Low carbohydrate – eat freely: watercress, lettuce, chicory, cucumber, olive, bell pepper and tomato.

››

Medium carbohydrate – limited portions: pumpkin, courgette, broccoli, carrot, collard greens, cauliflower, cabbage, aubergine and spinach.

›› Avoid: starchy vegetables such as potatoes and yams. •

Drinks: tea, coffee and water.

Calorie restriction Instead of concentrating on what is healthy to eat, calorie restriction focuses on the health-promoting effects of not eating, or restriction of food intake. In particular, calorie restriction exerts profound regenerative effects on mitochondria. In a similar way to exercise, calorie restriction decreases cellular and mitochondrial adenine triphosphate (ATP) and nicotinamide adenine dinucleotide (reduced) (NADH), with a corresponding rise in AMP-activated protein kinase (AMPK) and

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NAD+. AMPK (Cantó & Auwerx 2011) and NAD+ (Michan 2014) are both markers of low-energy status, yet their increased expression is far from a disaster – quite the opposite in fact; mitochondria actually thrive in their presence (Fernandez-Marcos & Auwerx 2011). AMPK and NAD+ are able to help activate anti-ageing SIRT proteins, trigger mitophagy and enable mitochondrial biogenesis (FernandezMarcos & Auwerx 2011; Palikaras & Tavernarakis 2014). Remember, mitophagy is required to digest worn-out, inefficient mitochondria, and mitochondrial biogenesis is needed to manufacture brand-new mitochondria. For more information on mitophagy and mitochondrial biogenesis, please refer to Chapter 4, ‘Mitochondrial Dynamics’. The problem with calorie restriction or fasting is how to balance the health benefits of a low-calorie intake against the risk of inducing nutritional deficiencies. A diet with the potential to address this benefit/risk issue is the fasting-mimicking diet. The fastingmimicking diet requires participants to every month undertake five consecutive days of calorie restriction, low sugar/protein and high unsaturated fat. Day 1 of the fasting-mimicking diet consists of 11 per cent protein, 46 per cent fat and 43 per cent carbohydrate, and provides around 1100 calories. Days 2–5 consist of 9 per cent protein, 44 per cent fat and 47 per cent carbohydrate, providing roughly 720 calories. Simple carbohydrate and protein intake are required to be kept to a minimum as they can block the regenerative effects of the diet. The majority of calories in the diet are provided by fat and complex carbohydrate. After three months on the fasting-mimicking diet, participants have been found to have reductions in body weight, blood pressure, body fat and insulin-like growth factor 1 (a marker for cancer risk). More pronounced improvements in blood glucose and lipid profiles have been observed in participants who were identified as being at greater risk of disease at the beginning of the diet. For more information on the fasting-mimicking diet please read the article by M. Wei et al. (2017).

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The Mediterranean diet The Mediterranean diet has a long history of improving blood sugar control and cardiovascular health outcomes. Patients adhering to the Mediterranean diet (rich in extra virgin olive oil) fare far better in health terms than those on a low-fat diet (Esposito et al. 2015). The Mediterranean diet is estimated to reduce the future chances of type 2 diabetes occurring by up to 23 per cent (Esposito et al. 2015). Many components of the Mediterranean diet support mitochondria in subtle but incredibly important ways. For example, plant compounds in the diet can activate mitochondria-supportive endogenous antioxidants, protect against aerobic glycolysis (Ferramosca & Zara 2014a) and can help block mitochondria reactive oxygen species (ROS) induction by pathogen-associated molecular patterns (PAMPs) from gut microbiota (Morris et al. 2015a). Additionally, the low glycaemic index of plant fibre, whole grains and nuts can help protect mitochondria from the extremely damaging effects of high blood sugar (Rodríguez-Rejón et al. 2014; Yan 2014). However, the star player for mitochondrial protection in the Mediterranean diet is extra virgin olive oil. The polyphenol hydroxytyrosol (contained in extra virgin olive oil) can support complexes of the mitochondrial electron transport chain, stimulate mitochondrial biogenesis and block the lipogenic switch, thereby assisting energy production by mitochondria (Peyrol et al. 2017; Priore et al. 2015). Olive oil polyphenols can also protect against neurodegeneration and depression by increasing the expression of neurotrophins such as nerve growth factor (NGF) (Carito et al. 2016). This neurotrophin helps to concentrate mitochondria at sites for axon growth in neurons. Without mitochondrial ATP, axon growth is inhibited (Hroudová & Fišar 2011). The Mediterranean diet is defined by UNESCO as being a shared experience in both preparation and consumption. The word ‘diet’ is derived from the ancient Greek word díaita – way of life. This definition of diet suggests that nourishment comes from a much broader sense

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of the word, to include food, community and lifestyle (Moro 2016). Interestingly, social enrichment is another potential source of the neurotrophin NGF (Branchi et al. 2006) found to support mitochondriadependent axon growth within neurons (Hroudová & Fišar 2011). Please be cautious of diets purporting to be Mediterranean diets which include white bread and excess sweetened food. Also, just because a restaurant is labelled ‘Italian’ or ‘Greek’, it does not mean that the menu items are all components of a healthy Mediterranean diet! For further information on the Mediterranean diet as defined by UNESCO, please read Bach-Faig et al. (2011).

GUIDELINES FOR THE MEDITERRANEAN DIET (UNESCO DEFINITION) Every meal: •

extra virgin olive oil – main fat of the diet. Hydroxytyrosol, a major polyphenol within extra virgin olive oil, helps to prevent the lipogenic switch by blocking endogenous fatty acid synthesis. Mitochondria would normally supply citrate/ acetyl-CoA for fatty acid synthesis. Hydroxytyrosol also supports the mitochondrial electron transport chain and mitochondrial biogenesis (Priore et al. 2015).

•

bread and cereals (wholegrain if possible) – fibre from whole grains and fruit and vegetables help reduce the absorption of PAMPs from gut bacteria. Mitochondria produce ROS in response to PAMPs (Morris et al. 2015a).

•

vegetables – some eaten raw

•

fruit – be careful of fruit with a high sugar content.

Eat a wide range of colours for both fruit and vegetables. The prooxidant properties of plant polyphenols trigger the synthesis of endogenous antioxidants which are protective to mitochondria (Stefanson & Bakovic 2014). The low glycaemic index of many of the fruit, vegetables and cereals in the diet can help protect mitochondria from high glucose-induced mitochondrial ROS (Yan 2014).

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Every day: •

6–8 glasses of water or teas

•

low-fat yoghurt or cheese

•

nuts

•

legumes

•

olives

•

herbs and spices

•

red wine in moderation – resveratrol from red wine increases the activity of SIRT anti-ageing enzymes. SIRT expression can support mitochondrial biogenesis (Markus & Morris 2008).

Per week consumption: •

seafood – more than twice a week. Omega-3 fatty acids from oily fish suppress the activity of the mitochondrial citrate carrier (CIC) (Ferramosca & Zara 2014a). CIC is a protein required to export mitochondrial citrate for endogenous fatty acid and cholesterol synthesis.

•

poultry, white meat and eggs – around twice a week

•

red meat and sugar – less than twice a week

•

processed meat – less than once a week. (Bach-Faig et al. 2011; Godos et al. 2017)

Vegetarian diet The benefits of the Mediterranean diet can be improved even further by cutting out meat consumption. The removal of meat from the Mediterranean diet leads to even better improvements in lipid profiles, with reductions in total cholesterol, low-density lipoprotein (LDL) cholesterol and insulin (Pagliai et al. 2017). Reductions in total and LDL  cholesterol and increases in high-density lipoprotein (HDL) cholesterol can help protect mitochondria within the cardiovascular system by decreasing oxidative stress and increasing autophagy (White et al. 2017).

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Mitochondria play an essential role in cholesterol metabolism by producing an oxysterol from cholesterol. This oxysterol is used to switch off excess cholesterol synthesis and to export cellular cholesterol to HDL. Therefore, well-functioning mitochondria will lead to improved HDL‑cholesterol levels (Parikh et al. 2015; White et al. 2017). At another level, the removal of cholesterol from foam cells in blood vessel walls to an HDL particle (efflux) requires a mitochondria-dependent pump. This pump is called an ATP-binding cassette (ABC) (Karunakaran et al. 2015). From the above it can be seen that improvements in blood cholesterol markers (from adhering to a vegetarian diet) will also correlate with improved mitochondrial function. Osteoarthritis patients adopting a meat-free, whole-food, plantbased diet have been found to experience a considerable reduction in pain. Their pain relief was seen as early as two weeks into the trial of the diet. The pain relief was thought to be due to the reduced intake of inflammatory mediators from animal produce. Animal products are rich in arachidonic acid, a fatty acid precursor to inflammatory prostaglandins and leukotrienes (Clinton et al. 2015). Many derivatives of arachidonic acid can initiate cell apoptosis via their negative effects on mitochondria (Yin et al. 2013). Additionally, when exposed to ROS, arachidonic acid can form the toxic lipid peroxide 4-hydroxynonenal. In chondrocytes of cartilage, 4-hydroxynonenal has been found to trigger mitochondrial-dependent apoptosis (Abusarah et al. 2017).

Low-GI (glycaemic index) diet The glycaemic index is a measure that categorizes carbohydratecontaining foods on how they influence a person’s blood glucose after a meal. Carbohydrate foods with a high GI will raise blood glucose more than those with a low GI. In fact there is a roughly a doubling in blood glucose following a meal containing high-GI carbohydrate foods compared to low-GI carbohydrate foods (Galgani et al. 2006). Mitochondria are particularly sensitive to raised blood glucose. High blood glucose can overwhelm the mitochondrial electron transport chain, leading to damaging levels of mitochondrial ROS

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(Yan 2014). Therefore, a low-GI diet can protect a cell from excessive mitochondrial ROS. There is a 33 per cent higher risk of type 2 diabetes for people when they consume a diet high in high-GI carbohydrate foods. That risk increases to 50 per cent when they consume a diet high in high-GI carbohydrates and low in fibre (Bhupathiraju et al. 2014). Table 16.1 Examples of low-, medium- and high-GI foods Low-GI foods Barley Apple Apple juice Orange Dates Vegetable soup Milk, full fat Yoghurt Soya beans Lentils Chickpeas Carrots, boiled

Medium-GI foods 28 36 41 43 42 48 39 41 16 32 28 39

Brown rice, boiled Muesli Porridge, rolled oats Pineapple, raw Mango, raw Banana, raw Pumpkin, boiled Honey Sweetcorn Sweet potato, boiled Couscous

High-GI foods 68 57 55 59 51 51 63 61 52 63

White bread Wholemeal bread Cornflakes Instant porridge Potato, boiled Rice milk Rice crackers/crisps Glucose

75 74 81 79 78 86 87 103

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Source: International Tables of Glycemic Index and Glycemic Load Values (Atkinson et al. 2008)

The DASH diet The DASH (dietary approaches to stop hypertension) diet has a 20‑year proven track record of helping hypertensive patients to reduce their blood pressure. The DASH diet is rich in fruit, vegetables, nuts and low‑fat dairy products, and low in saturated fat and sugar. The DASH diet places an emphasis on foods which are good sources of fibre, potassium, magnesium and calcium. The DASH diet is not a lowsodium diet, but lowered sodium intake can help improve the benefits of the diet. Patients on the DASH diet may see their systolic blood pressure reduce by as much as 12mmHg (Moore et al. 2001; Steinberg et al. 2017).

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Mitochondrial ROS have been reported to be implicated in hypertension (Dikalov & Ungvari 2013), and like the Mediterranean diet, the emphasis on fruit and vegetables and low glycaemic index will support mitochondria. Polyphenols from fruit and vegetables drive the synthesis of endogenous antioxidants which are protective to mitochondria (Stefanson & Bakovic 2014). Low glycaemic index foods protect mitochondria from excessive NADH supply to the electron transport chain – excess NADH supply to mitochondria increases mitochondrial ROS and leads to dysfunction (Yan 2014). Foods recommended on the DASH diet include: • • • • • •

fruit and vegetables nuts, seeds, beans and peas low-fat dairy products lean meats, poultry and fish grains – preferably wholemeal or brown rice fats and oils: the DASH study included 27 per cent of calories derived from fat. (National Heart, Lung, and Blood Institute 2017)

Sweets and added sugar are not recommended, or should be kept to a minimum. Limiting sodium intake to 1500mg per day can lead to further improvements in the diet’s beneficial effect on blood pressure (National Heart, Lung, and Blood Institute 2017).

The low-FODMAP diet Many patients with fatigue also present with gastrointestinal symptoms such as IBS, bloating and disturbances of microbiota. The FODMAPs (fermentable oligo-, di- and monosaccharides and polyols, which include fructose, lactose, sorbitol, mannitol, fructans, galactans, raffinose and stachyose) are known to exacerbate fatigue symptoms in sensitive individuals (Barrett & Gibson 2010; Berstad & Valeur 2016). FODMAPs (in association with disturbed gut microbiota) can drive inflammation and intestinal permeability (Zhou et al. 2017). Once in

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general circulation, PAMPs from disturbed gut microbiota can activate toll-like receptors of the innate immune system which in turn promote mitochondrial dysfunction (Morris et al. 2015a). Below is a list of FODMAPS and examples of food sources to avoid if adhering to a low-FODMAP diet. • • • • •

Fructose: honey, apples and pears Fructans: wheat, rye, onion and garlic Galactans: cabbages and legumes Lactose: milk and milk products Polyols (sorbitol and mannitol): stone fruits, mushrooms and sweeteners. (Barrett & Gibson 2010; Khan et al. 2015)

The MIND diet The MIND diet, or the Mediterranean–DASH Intervention for Neurodegenerative Delay to state its full name, is exactly what it says – it’s a hybrid of the Mediterranean diet and DASH diet for hypertension. Additionally the MIND diet focuses on including berries and green leafy vegetables – both of which are supported by evidence backing up their use to support dementia patients. Spinach, kale or collard greens are recommended by the MIND diet to be consumed at least six times a week. Green leafy vegetables have been reported to slow age-related cognitive decline due to their high content of beneficial nutrients. Of particular interest to neurodegeneration is the high vitamin K content of spinach, kale or collard greens. This is due to the similarity of vitamin K to CoQ10, the electron carrier of the mitochondrial electron transport chain. Both compounds are quinones – vitamin K is known as phylloquinone, and CoQ10 is known as ubiquinone. Researchers are finding that it is highly likely that vitamin K could be supportive to stressed mitochondria by acting as an electron carrier in place of CoQ10 (Vos et al. 2012). Strawberry, bilberry, blueberry, blackberry, blackcurrant, cranberry and mulberry are all fruits with neuroprotective properties (Subash et al.

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2014). The anthocyanin content of bilberry, blueberry and cranberry, in particular, has been observed to protect neuronal mitochondria in an in vitro study of Parkinson’s disease (Yao & Vieira 2007). The MIND diet focuses on 15 food groups – ten healthy groups to increase and five unhealthy groups to decrease.

THE MIND DIET GUIDELINES Food groups to increase

Food groups to decrease

Green leafy vegetables

Red meat

Other vegetables

Butter and margarine

Nuts

Cheese

Berries

Pastries and sweets

Beans

Fried or fast food

Wholegrains Fish Poultry Olive oil Wine (1 glass per day) (Morris et al. 2015b)

The Swank diet: a low saturated fat diet The Swank diet has a long history of providing benefit for patients managing with multiple sclerosis. It has been found that people on the diet were 42 per cent less likely to have a worsening of their disability than those not on the diet (Hadgkiss et al. 2015). Impressively, after 34 years on the Swank diet, patients displayed vastly better health than those not on the diet (Hadgkiss et al. 2015). However, it is only recently that science has been able to start to make some sense of the mitochondrial benefits of the Swank low-fat diet. These recent findings appear to put mitochondrial dysfunction at the heart of multiple sclerosis pathology. The missing piece in the jigsaw is the observation that multiple sclerosis patients have been found to have extreme difficulty 142

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metabolizing dietary fat through mitochondrial β-oxidation. The outcome of this difficulty is for organelles called peroxisomes to carry out fatty acid β-oxidation instead of mitochondria. Acetyl-CoA generated by peroxisomes cannot be used for energy and so is used to synthesize very long chain fatty acids (22 carbon chains or longer). As multiple sclerosis progresses, the circulating levels of very long chain fatty acids increase (Senanayake et al. 2015). A study on an animal model of multiple sclerosis observed that inhibition of fatty acid metabolism resulted in a reduction in disease symptoms and less inflammation and demyelination (Shriver & Manchester 2011). In the context of the above discovery of β-oxidation defects in multiple sclerosis patients, reducing the fatty acid load on struggling mitochondria and peroxisomes makes sense. A reduction in fatty acid load will result in less synthesis of very long chain fatty acids by peroxisomes, and supports the low-fat protocol of the Swank diet. Out of interest, very long chain fatty acids are used in the synthesis of the myelin sheath – could an excess of these fatty acids undermine the myelin sheath, by altering the balance of fatty acids within the myelin sheath? It is highly likely that the low-fat Swank diet supports mitochondria of multiple sclerosis patients by lessening the fatty acid load on struggling mitochondria and peroxisomes. In this way the β-oxidation defect in mitochondria would be less challenged. In addition to peroxisomes supplying endogenous fatty acids, the inflammatory nature of the typical Western diet can lead to mitochondria initiating endogenous fatty acid synthesis. Autoimmune Th17 T cells need endogenous fatty acids, which are usually created from citrate export from mitochondria (Berod et al. 2014). Mitochondrial dysfunction seen in multiple sclerosis enables peroxisomes to effectively elongate dietary fatty acids to very long chain fatty acids (Senanayake et al. 2015) which could potentially further support autoimmune Th17 T cells. A typical Western diet can also lead to increases in circulating leptin. Excess leptin leads to the suppression of immune self-tolerance, due to its suppressive effect on T regulatory cells. Therefore increased circulating leptin can shift T cell expression toward the autoimmune Th17 phenotype (S. Wang et al. 2013). 143

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SWANK DIET GUIDELINES •

No processed foods that contain saturated fat or hydrogenated fat

•

Limit all saturated fat to 15g per day

•

Unsaturated fat intake to be between 20g and 50g per day

•

Unlimited fruit and vegetables

•

No red meat allowed in the first year (pork is considered a red meat)

•

80g of red meat allowed once a week after the first year

•

White meat poultry only – remove skin

•

White fish

•

Limit fatty fish to 50g per day. (Swank MS Foundation 2015)

Another multiple sclerosis diet which has been gaining a lot of publicity and attention is Wahls’ paleo diet, formulated by Dr Terry Wahls. Using herself as a patient, Dr Wahls devised a diet to help her recover from her own MS. Dr Wahls claims that the components of her diet feed and assist mitochondria – although she is not specific about the fine detail of the mechanisms involved. Dr Wahls has co-authored several papers in support of her diet and has a TED talk available online about her diet‑led recovery from multiple sclerosis. The Wahls diet specifies a high intake of leafy green vegetables per day. Dr Wahls suggests three cups a day of leafy greens, such as spinach, kale or collard greens. The mitochondrial benefits of these vitamin K-rich vegetables are listed above in the MIND diet section.

Vitamin K and green leafy vegetables What is fascinating about vitamin K in relation to multiple sclerosis is its ability to protect developing oligodendrocytes. Developing oligodendrocytes are the precursors to oligodendrocytes, the cells which provide a myelin sheath to axons of neurons of the central nervous system. Vitamin K is able to block the effects of inflammatory mediator

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12-lipoxygenase on vulnerable developing oligodendrocytes and thereby maintain the integrity of the myelin sheath (Li et al. 2009). Alzheimer’s disease, Parkinson’s disease and diabetes all have been shown to have the activation of 12-lipoxygenase as part of their pathology. Additionally, metabolites of 12-lipoxygenase are toxic to mitochondria through excessive nitric oxide production and glutathione depletion (Dobrian et al. 2011). An important vitamin K dependent protein with regard to neuroinflammation is Gas6. Gas6 has been showing a lot of promise in many studies for its ability to reduce neuroinflammation and to defend against the loss or degradation of the myelin sheath surrounding neurons. Furthermore, Gas6 can help to protect neurons from the toxicity of amyloid β, the misfolded protein implicated in the pathology of Alzheimer’s disease (Bellan et al. 2016). From the above, it can be seen that green leafy vegetables, and their vitamin K content, hold a lot of promise for protecting against neurodegeneration, inflammatory disease and mitochondrial dysfunction. It is known that prolonged antibiotic therapy can induce a vitamin K deficiency (Aziz & Patil 2015). Therefore, it may be wise to monitor vitamin K levels after antibiotic therapy.

Polyamine-reduced diet The polyamines (spermine, spermidine and putrescine) are a group of compounds known as biogenic amines. Polyamines have numerous functions in the body and can be synthesized internally, produced by intestinal bacteria, or ingested in food products. Polyamines are required for normal growth and development, but levels are raised in cancer and in patients suffering from pain (Bell et al. 2012; Cipolla et al. 2010). Polyamines have the ability to increase the activity of the glutamate receptor (N-methyl-D-aspartate receptor) and so increase a person’s sensitivity to pain. Magnesium exerts the opposite effect on glutamate receptors, giving the mineral its analgesic property (Bell et al. 2012). Over-activation of the glutamate receptor leads to high levels of cytosolic calcium and a subsequent uptake of calcium by mitochondria.

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Excessive mitochondrial calcium results in increases in mitochondrial superoxide and an escalation in pain signalling. Blocking mitochondrial calcium uptake or mitochondrial superoxide production has been reported to decrease pain (Kim et al. 2011). This means that, by lowering glutamate receptor activity, a low polyamine diet will put less stress on mitochondria within sensory nerves, thereby helping to reduce persistent pain. Diets which are low in polyamines are being explored for pain relief. Ideally, a low-polyamine diet should be concomitant with an intervention to address gastrointestinal dysbiosis, so that levels of polyamine-synthesizing bacteria can be reduced.

RESTRICTED FOODS FOR A POLYAMINE-REDUCED DIET (CAN INCLUDE ONLY TWO DAYS A WEEK) •

Calamari, squid, oysters, mussels, crab

•

Liver mousse, duck-liver pâté, pork liver pâté

•

Garlic, chervil, tarragon, cabbage, broccoli, parsley

•

Mushrooms, green peas, aubergine, ripe tomatoes, courgette and marrow

•

Oranges, hazelnuts, almonds, pistachios, peanuts, bananas

•

Sweet Cantal cheese with rind, Roquefort, Comté and

•

Wheat, mustard, tinned gherkins, tomato concentrate,

Saint‑Nectaire cheese instant mashed potatoes •

Minced spinach, lentils, chickpeas, ratatouille. (Cipolla et al. 2010)

The Feingold diet The Feingold diet was devised by Dr Benjamin Feingold after he noticed an improvement in autistic children’s behaviour when they avoided the drug aspirin. This led to Dr Feingold advising the restriction of other aspirin-like compounds – particularly food colourings.

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The effect of food colouring is often trivialized, but animal studies have found that they can have a catastrophic effect on mitochondrial energy production (Reyes et al. 1996). No wonder many children struggle with food colouring – with or without autism. Compounds eliminated in the Feingold diet are: • synthetic colours and preservatives manufactured from petroleum • salicylate-containing foods (e.g. almonds, berries, cucumber, apples and oranges) • artificial sweeteners. (Ward et al. 2013)

Conclusion Diets are often considered by the general public in terms of weight loss – not as powerful tools to support health in their own right. From the above dietary descriptions, it can be seen that many diets work at numerous different levels within our metabolism. Importantly, mitochondria are once again the beneficiaries of these well-constructed, evidence-based health interventions.

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17 Laboratory Tests and Biomarkers Related to Mitochondrial Function

This chapter contains examples of laboratory tests which can help form part of a practitioner’s assessment of a client’s overall and mitochondrial health. In personalized nutrition, the exact combination of tests chosen will be influenced by the unique signs, symptoms and case history details of the individual client. After each test I have included a short list of laboratories that the test is available from. These lists are not exhaustive and the tests may be available elsewhere. GPL-TOX: toxic environmental test

GPL-TOX is a toxic organic exposure profile that screens for the presence of 168 different toxic chemicals including organophosphate pesticides, phthalates, benzene, xylene, vinyl chloride, pyrethrin insecticides, and others. Organophosphates are toxic to the complexes of the electron transport chain, reduce adenosine triphosphate (ATP) synthesis, undermine calcium uptake and promote cell death via apoptosis (Karami-Mohajeri & Abdollahi 2013). Once dysfunctional, mitochondria become even more sensitive than healthy mitochondria

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to environmental toxins. This profile also includes tyglyglycine (TG), a marker for mitochondrial disorders resulting from mutations of mitochondrial DNA (mtDNA). Available from: UK – Biolab Medical Unit: www.biolab.co.uk US – Great Plains Laboratory Inc: www.greatplainslaboratory.com Cyrex array 7

Cyrex array 7 is a screen for neuro-autoimmunity. In the profile, antibodies against alpha and beta tubulin are measured. Alpha and beta tubulin are proteins which form part of the cytoskeleton within a cell. The cytoskeleton is like an internal scaffold which gives a cell form and shape. It is vital to maintain the integrity of the cytoskeleton in neurons, as the axon structure will collapse if the cytoskeleton is damaged or compromised. Microtubules of the cytoskeleton also provide the ‘railway tracks’ which allow mitochondria to travel along the axon to the synapse. Please see Chapter 4, ‘Mitochondrial Dynamics’, for more information. Problems with tubulins are often seen in Alzheimer’s disease and can lead to a dysfunctional cytoskeleton within a neuron; a well‑functioning cytoskeleton is important as mitochondria travel along the microtubules of the cytoskeleton to reach the neuronal synapse. Available from: UK – Regenerus Laboratories: regeneruslabs.com US – Cyrex Laboratories: www.cyrexlabs.com Oxidative Stress 2.0

Oxidative Stress 2.0 is a blood and urine profile which measures the presence of lipid peroxides and 8-hydroxydeoxyguanosine (8-OHdG), the activity of superoxide dismutase (SOD), as well as several other markers for oxidative stress. Lipid peroxides are known to be particularly toxic to mitochondria, having been shown to reduce ATP synthesis by as much as 30 per cent,

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in a study examining Alzheimer’s disease (Aufschnaiter et al. 2017). This large reduction in mitochondrial energy is not surprising as lipid peroxides have been observed to have a strong affinity for mitochondrial protein binding. It is estimated that roughly a third of the lipid peroxide 4-hydroxynonenal, produced by lipid peroxidation, will target and inhibit mitochondrial proteins (Zhong & Yin 2015). 8-OHdG is a marker for oxidative damage to DNA – including mtDNA. In a study examining oxidative stress in type 2 diabetes patients, 8-OHdG levels correlated with the deletion or loss of mtDNA (Suzuki et al. 1999). SODs are a family of three SOD enzymes which defend against the damaging effects of the superoxide radical. SOD2 is the mitochondrial isoform of the enzyme. Low levels of SOD activity are associated with many health conditions including diabetes (Chattopadhyay et al. 2015), osteoarthritis (Gavriilidis et al. 2013), hypertension (Dikalova et al. 2015) and accelerated ageing (Paul et al. 2007). Available from: UK and Europe – Genova Diagnostics Europe: www.gdx.net/uk US – Genova Diagnostics: www.gdx.net Metabolic syndrome profile, waist-to-hip ratio and BMI (body mass index), HOMA insulin resistance calculator and Advanced NMR Lipids LipoProfile

The profiles listed below all contain key markers of mitochondrial dysfunction. Metabolic syndrome, insulin resistance, type 2 diabetes, neurodegeneration, heart disease, high cholesterol and hypertension can all be traced back to failing mitochondria. Environmental toxins, high calorie intake, glucose and saturated fat excess are possible mechanisms linking these conditions to mitochondrial dysfunction (Bhatti et al. 2017; Jha et al. 2017). Autoimmunity has also been found to have a strong association with metabolic syndrome (Haghikia & Gold 2016; Kerekes et al. 2014). As we have seen in Chapter 9, ‘Altering Immune Function’, mitochondria in ‘anabolic mode’ can support the function of autoreactive Th17 T cells (Berod et al. 2014). Metabolic

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syndrome is linked to factors which help mitochondria support a shift toward saturated fat synthesis (Ferramosca & Zara 2014b) to support autoimmunity. For further information on how these profiles are associated with mitochondrial dysfunction, please read Chapter 18, ‘Insulin Resistance and Type 2 Diabetes’. Additionally, Bhatti et al. (2017), Di Meo et al. (2017) and Jha et al. (2017) provide excellent review papers which discuss the connection between mitochondria, insulin and chronic disease. Metabolic syndrome profile

The metabolic syndrome profile measures: • Glucose – raised blood glucose is toxic to mitochondria. Raised glucose can overwhelm the mitochondrial electron transport chain, leading to increases in mitochondrial reactive oxygen species (ROS) (Yan 2014). • HbA1C – raised glycated haemoglobin associated with low mitochondrial function (Saner et al. 2018). • Insulin – see above reviews for the complex association of insulin with mitochondria. • CRP/ hsCRP – cardiomyocytes have been found to suffer increased mitochondrial dysfunction and ROS in the presence of CRP (Lee et al. 2016). • Adiponectin – adipokine which raises PGC-1α, a cofactor necessary for mitochondrial biogenesis (Iwabu et al. 2010). • Triglycerides – high triglycerides, cholesterol and low-density lipoprotein cholesterol can be indicative of an anabolic state (biosynthetic) (Sieber & Spradling 2017). Mitochondria need to undergo a lipogenic switch to enable the export of citrate/ acetyl‑CoA for the synthesis of cholesterol and triglycerides. • Cholesterol – mitochondria produce oxysterols from cholesterol. Oxysterols in turn control the gene expression of proteins which regulate cholesterol synthesis and removal (Olkkonen et al. 2012).

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• HDL (high-density lipoprotein) cholesterol – mitochondrial oxysterols control cholesterol removal from cells to help form HDL. In return, increased HDL has been observed to be supportive to mitochondria. • LDL (low-density lipoprotein) cholesterol. • Non-HDL cholesterol. When assessed together, all the markers of the metabolic syndrome profile are considered representative of insulin resistance and metabolic syndrome. Available from: UK – The Doctors Laboratory: www.tdlpathology.com US – SpectraCell Laboratories: www.spectracell.com (pre-diabetes test with similar markers to the metabolic syndrome profile) Waist-to-hip ratio and BMI (body mass index)

Both these calculations can be useful additions to insulin resistance laboratory tests. There is a strong negative relationship between BMI and mitochondrial activity in adipose tissue. In a study measuring BMI in females, increased BMI correlated with decreased mitochondrial electron transport chain activity in adipocytes (Fischer et al. 2015). HOMA insulin resistance calculator

The relationship between fasting insulin and glucose levels can be used to determine a person’s degree of insulin resistance, insulin sensitivity and β-cell function. The theory behind the readings is known as the homeostasis model assessment (HOMA). Inputting laboratory results for fasting insulin and glucose into the HOMA calculator can be used to determine a person’s degree of insulin resistance, insulin sensitivity and β-cell function. The theory behind the readings is known as the homeostasis model assessment: • HOMA-IR – insulin resistance • HOMA-β – β-cell function • HOMA-S – insulin sensitivity.

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The HOMA calculations are considered to be a more practical solution to assessing a person’s glucose tolerance than the oral glucose tolerance test (Onishi et al. 2010). HOMA-IR is linked to waist:hip ratio, body mass index and total and percentage body fat. HOMA-S is negatively linked to these parameters. HOMA-S levels decline as waist:hip ratio, fasting glucose and total cholesterol all increase (Garg et al. 2011). A free calculator to assess a person’s insulin resistance, insulin sensitivity and β-cell function, from fasting insulin and glucose levels, can be downloaded from www.dtu.ox.ac.uk/homacalculator/ download.php

Figure 17.1 The HOMA Calculator7

The HOMA Calculator provides results for %B (β-cell function), %S (insulin sensitivity) and IR (insulin resistance). Enter the results of plasma glucose and insulin to calculate the results. Disclaimer: The HOMA Calculator is intended for use by healthcare professionals to assist in the assessment of β-cell function and insulin sensitivity. It may be of assistance in the management of insulin resistance or type 2 diabetes but is not a replacement for formal medical assessment and not intended for use by patients unless in consultation with their trained medical adviser.

7

The HOMA Calculator is included with the kind permission of The Diabetes Trials Unit at the University of Oxford’s Radcliffe Department of Medicine.

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Advanced NMR Lipids LipoProfile

The Advanced NMR Lipids LipoProfile includes subfractions of cholesterol metabolism, which give more detailed information regarding mitochondrial activity within the cardiovascular system. The concentration of HDL particle size and number have been reported to correlate with improved mitochondrial ATP synthesis. Conversely, small LDL particle size and number have been found to correlate with a reduction in mitochondrial activity and ATP synthesis (Parikh et al. 2015). Available from: UK – Invivo Clinical: www.invivoclinical.co.uk US – Cleveland HeartLab: www.clevelandheartlab.com Chest pain profile

Heart failure has a strong association with mitochondrial dysfunction. Mitochondria are required to provide ATP for cardiac muscle contractions. Mitochondria also act as facilitators of cardiac muscle death via apoptosis (Rosca & Hoppel 2013). • Myoglobin – mitochondrial respiration modulator (HendgenCotta et al. 2014) • CK MB Fraction – marker for myocardial infarction • Troponin T – marker for cardiomyocyte apoptosis (apoptosis is mitochondria dependent) (Kocak et al. 2015). Available from: UK – The Doctors Laboratory: www.tdlpathology.com US – Cleveland HeartLab: www.clevelandheartlab.com (as individual markers) Proinflammatory cytokine profile

Proinflammatory cytokines stimulate the production of mitochondrial superoxide (Cao et al. 2013). In turn, mitochondrial ROS drive the synthesis of proinflammatory cytokines (Naik & Dixit 2011).

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Interleukin 17

May be indicative of Th17 T cell polarization and potential autoimmunity. Th17 cells require aerobic glycolysis to function (Palmer et al. 2015). Aerobic glycolysis relies on the export of citrate from mitochondria. The proinflammatory cytokine profile and Interleukin 17 are available from: UK – Invivo Clinical: www.invivoclinical.co.uk US – R.E.D. Laboratories: www.redlabs.com (University of Nevada) Europe – R.E.D. Laboratories: www.redlabs.com (Belgium) Methylation panel

A comprehensive profile assessing critical methylation and glutathione pathways. Altered DNA methylation will have a negative impact on mitochondrial function (McGowan & Roth 2015). Available from: UK – Invivo Clinical: www.invivoclinical.co.uk US – Health Diagnostics and Research Institute: www.hdri-usa.com Europe – European Laboratory of Nutrients: www.europeanlaboratory.nl GI-MAP and gut permeability profile

Gut microbiota and mitochondria are intimately connected via three mechanisms: the first is their common bacterial ancestral heritage; second, through the beneficial effects on mitochondria of short-chain fatty acids from the fermentation of fibre; and third, through the action of bacterial pathogen-associated molecular patterns (PAMPs), which increase the production of mitochondrial ROS. In turn, mitochondrial ROS and dysfunction has been associated with intestinal permeability (Saint-Georges-Chaumet & Edeas 2016). GI-MAP

The GI Microbial Assay Plus (GI-MAP) was designed to assess a patient’s microbiome from a single stool sample. Particular attention is paid to microbes that cause disease or that disrupt normal microbial balance,

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contributing to perturbations in the gastrointestinal flora and leading to illness. Imbalances of a patient’s microbiome may become sources of PAMPs, which are associated with inflammation and fatigue. Available from: UK – Invivo Clinical: www.invivoclinical.co.uk US – Diagnostic Solutions Laboratory: www.diagnosticsolutionslab.com Gut permeability profile

A permeable gut will lead to an increase in fatigue, inducing PAMPs to cross the intestinal barrier. Available from: UK – Biolab Medical Unit: www.biolab.co.uk US – Health Diagnostics and Research Institute: www.hdri-usa.com Europe – European Laboratory of Nutrients: www.europeanlaboratory.nl PET scan – Alzheimer’s disease and Parkinson’s disease diagnosis

Until recently, it has been extremely difficult to diagnose Alzheimer’s disease and Parkinson’s disease from neuroimaging tests or, in fact, any tests. Frequently, both diseases have been diagnosed from symptoms, or a response to medication. With the development of the PET (positron emission tomography) scan there have been great advances in the detection and analysis of neurodegeneration. PET scans use radioactive tracers to identify the parts of the brain associated with each condition. An exciting development has recently occurred with regard to the use of PET scans to diagnose mitochondrial dysfunction in Alzheimer’s disease and Parkinson’s disease (Tsukada 2016; Tsukada et al. 2016). At the moment the work is limited to laboratory animals, but hopefully the work should be able to be expanded for use with human patients. PET scans should be organized through a patient’s neurologist. Please note that not all health authorities will have access to PET scanning facilities.

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Phospholipase A2

Phospholipase A2 (PLA2) is elevated in a wide range of inflammationrelated disorders and is considered a good marker for increased risk of developing or worsening of inflammatory conditions. Phospholipases have been found to be over-activated in neurodegenerative conditions (Kanfer et al. 1998). Some sub-types of PLA2 have been shown to degrade cardiolipin (Adibhatla & Hatcher 2006), a vital phospholipid needed to help maintain the integrity of the inner mitochondrial membrane. Degradation of cardiolipin may lead mitochondria to trigger apoptosis (Ascenzi et al. 2011). Available from: UK – Biolab Medical Unit: www.biolab.co.uk US – Great Plains Laboratory Inc: www.greatplainslaboratory.com Organic acids test – nutritional and metabolic profile

The organic acids test provides a wide range of markers, with many specifically aimed at providing detailed information about mitochondrial function. The test includes markers for: • • • •

glycolysis the TCA (tricarboxylic acid) β-oxidation in mitochondria electron transport chain function.

The organic acids test markers 2-oxoglutaric, citric, 4-hydroxybenzoic, 4-hydroxyphenylacetic, hippuric, adipic and suberic acids have all been reported to be abnormal in a study examining the urine of autistic children (Kałużna-Czaplińska 2011). 4-hydroxybenzoic, 4-hydroxyphenylacetic and hippuric acids are all markers for intestinal bacterial overgrowth. Adipic and suberic acids are markers for altered fatty acid metabolism and β-oxidation in mitochondria. 2-oxoglutaric and citric acids are markers for the TCA in mitochondria. From the above study, it can be seen that there are abnormal levels of energy metabolism-related organic acids found in autism

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spectrum  children. These findings appear to confirm the emerging evidence suggesting a strong link between autism spectrum disorders and mitochondrial dysfunction (Griffiths & Levy 2017). Available from: UK – Biolab Medical Unit: www.biolab.co.uk US – Great Plains Laboratory Inc: www.greatplainslaboratory.com

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18 Insulin Resistance and Type 2 Diabetes

Insulin resistance and type 2 diabetes are endemic in Western society, resulting from a combination of over-consumption, poor dietary choices and our sedentary lifestyles. The conditions lead to pathological changes, not just in the β-cells of the pancreas, but in many other cells and tissue. The liver, adipose tissue, monocytes, inflammation, mitochondria and neuronal pathways all play their part in insulin resistance and type 2 diabetes (Muoio & Newgard 2008). Shockingly, around 5 per cent of worldwide deaths each year occur due to diabetic complications. According to Andrade et al. (2015), if the current worrying trend continues, there will be 366 million people with type 1 or type 2 diabetes by the year 2030. Sedentary lifestyles, combined with over-nutrition, will mean that the body’s natural anti-ageing reparative processes are disabled. SIRT1, the anti-ageing protein, plays a vital role in the healthy functioning of these processes. Please see the sections ‘Nicotinamide riboside’ and ‘Resveratrol’ below for more information on SIRT1 and type 2 diabetes. Mitochondria perform a central role in pancreatic β-cell function and the production of insulin. Additionally, mitochondria are at the

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very heart of how insulin resistance affects target tissues and organs (in insulin target tissues, insulin is required to allow glucose access to cells). Both β-cells and insulin target tissue are critically compromised by lack of exercise and excess consumption of simple carbohydrate and saturated fat (Muoio & Newgard 2008). This so-called ‘over-nutrition’ is disastrous for the health of our mitochondria. It’s such an irony that over-nutrition, with the typical Western diet, can lead to chronic malnutrition and ill-health. Glucose

Mitochondrial ATP increase

Closing of potassium channel

Insulin secretion

Increased β-cell calcium

Opening of calcium channel

Figure 18.1 The steps from glucose to insulin secretion in pancreatic β-cells

When glucose enters a pancreatic β-cell, mitochondria swiftly respond to glucose by rapidly increasing ATP (adenosine triphosphate) output. ATP subsequently triggers insulin secretion by closing a potassium channel, which leads to an influx of calcium. It is raised cellular calcium that then activates enzymes to enable insulin secretion (Tarasov et al. 2004).

Extracellular ATP – a surprising factor to control insulin synthesis Outside a cell, ATP changes in its role from an energy carrier to a chemical transmitter. Surprisingly, extracellular ATP helps to regulate pain, the immune system and pancreatic β-cell function. ATP works both inside and outside a pancreatic β-cell. Inside the β-cell, ATP triggers insulin secretion. Outside the β-cell, ATP is co‑released alongside insulin and performs as a regulator of β-cells, by acting on purine receptors (remember, adenosine is a purine) (Tengholm 2014).

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Low ATP leads to compromised insulin secretion Mitochondria within pancreatic β-cells are vulnerable to oxidative stress. If mitochondrial ATP is compromised, then there may be insufficient ATP to allow for insulin secretion. Poor insulin secretion is seen in late-stage type 2 diabetes. The sources of oxidative stress can be inflammation, high sugar/simple carbohydrate intake, obesity and high saturated fat, to name but a few. Frustratingly, once under stress, mitochondria can also become a significant source of reactive oxygen species (ROS), leading to a downward spiral of β-cell dysfunction (Cerf 2013).

Metabolic inflexibility and insulin resistance The involvement of mitochondria in insulin resistance is not typically considered in the aetiology of the disease. However, the inflexibility of mitochondria to switch from fat-burning β-oxidation to glucoseburning oxidative phosphorylation is at the very core of insulin resistance (Szendroedi et al. 2011). For a more in-depth look at how metabolic inflexibility in mitochondria leads to insulin resistance, please read Chapter 5, ‘Maintaining Allostasis’. Reductive stress

Over-nutrition, with the excessive calorie intake of a typical ‘Western’ diet, can lead to a corresponding excess amount of nicotinamide adenine dinucleotide (reduced) (NADH) being produced by the tricarboxylic acid (TCA) cycle. The negative mitochondrial effects of over-nutrition are not typically considered. However, on entering into Complex I of the mitochondrial electron transport chain, this excess NADH overwhelms Complex I, causing an ‘overspill’ of electrons. Once out of the safety electron transport chain, these electrons bind to oxygen to form the oxygen radical superoxide. In this way, excessive calorie intake can lead to mitochondrial ROS production (Yan 2014). The chronic stress induced in mitochondria by a lifetime of excessive

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calorie intake may be a major cause of mitochondrial ROS driving mitochondrial dysfunction. Too much of the reduced energy carrier NADH compared to its oxidized form nicotinamide adenine dinucleotide (oxidized) (NAD+) is known as ‘reductive stress’, not oxidative stress. Ironically, too much reductive stress will lead to oxidative stress. Worryingly, increasing amounts of mitochondrial ROS and NADH can cause the inhibition of glycolysis, driving glucose down pathways which lead to further oxidative stress (Yan 2014).

Nutrients to consider to reduce the risk of insulin resistance and type 2 diabetes Certain dietary supplements may be helpful in metabolic disorders due to various mechanisms and not least because of their role in supporting mitochondrial function. α-Lipoic acid

In type 2 diabetes and metabolic syndrome it is thought that mitochondrial ROS and poor β-oxidation of fats in mitochondria could be two causes of insulin resistance (Goodpaster 2013). To counter these issues, α-lipoic acid can help reduce mitochondrial ROS (Valdecantos et al. 2012), protect against fat toxicity (lipotoxicity) (Kim et al. 2013) and improve insulin sensitivity (Woo et al. 2005). The saturated fatty acid palmitate is particularly toxic to pancreatic β-cell mitochondria (Wiederkehr & Wollheim 2009), and so the ability of α-lipoic acid to help prevent lipotoxicity will also be extremely important for the health and function of pancreatic β-cell mitochondria. Magnesium

Mitochondria in pancreatic β-cells have a unique sensitivity to cellular glucose and calcium, and they will respond by producing more ATP. Magnesium can help regulate pancreatic β-cells, and protect them from excess calcium (Chhabra et al. 2012; Clark et al. 2017; Elamin & Tuvemo 1990; Günther 2010). Although there is no direct research on the

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protective effect of magnesium for β-cell mitochondria, the fact that all mitochondria in all cells rely on the protection that magnesium provides (Haworth & Hunter 1979) suggests magnesium is an important nutrient. Omega-3 fatty acids: docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)

Omega-3 fatty acids are known to change the phospholipid profile of mitochondrial membranes. With omega-3 fatty acids displacing omega-6 fatty acids from mitochondrial membranes, mitochondria become more efficient at producing ATP. This is seen most clearly in the mitochondria of a diabetic heart (Jeromson & Hunter 2014; Katyare & Mali 2016). Supplementation with the omega-3 fatty acids DHA and EPA is associated with dramatic improvements in many of the factors linked to insulin resistance, metabolic syndrome and type 2 diabetes. These improvements are: • 43 per cent increase in insulin sensitivity • 25 per cent decrease in fasting insulin • lower C reactive protein (a liver-derived compound, which correlates with the level of inflammation in the body) • lower night-time systolic blood pressure • lower free fatty acids. (Albert et al. 2014)

Dietary and endogenous lipids have a profound influence (both good and bad) on insulin resistance and diabetes. Dietary cholesterol and endogenous synthesis of saturated fat can trigger inflammatory signals within the adipose tissue of macrophages (white blood cells/leukocytes that engulf and digest microscopic bodies). This lipid-induced inflammation is thought to be a major cause of insulin resistance (Wei et al. 2016). The synthesis of endogenous saturated fat depends on mitochondria working in ‘anabolic mode’, exporting citric acid/acetyl-CoA – again encouraged by inflammation. Please read Chapter 7, ‘Synthesizing Cellular Components’, for more detailed information.

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Omega-3 fatty acids can block the synthesis of endogenous saturated fat and so play a major role in protecting against insulin resistance and diabetes (Ferramosca & Zara 2014a). Conjugated linoleic acid (CLA) and extra virgin olive oil

CLA is thought to exert its fat-burning effect via the up-regulation of β-oxidation and heat generation within mitochondria (Baraldi et al. 2016). In addition to supporting mitochondrial β-oxidation, CLA can up‑regulate the production of new mitochondria through mitochondrial biogenesis (Kim & Park 2015). Frustratingly, CLA alone can increase insulin resistance, but, taken in combination with phenol-rich extra virgin olive oil, this negative effect is removed. Hydroxytyrosol, the main polyphenol in extra virgin olive oil, has been found to help prevent insulin resistance in laboratory animals (Baraldi et al. 2016). Curcumin from the spice turmeric

Curcumin, and related curcuminoids, are a group of polyphenols extracted from the spice turmeric. Turmeric has a long history of usage in Ayurveda, a system of medicine developed in India around 3000 years ago. In more recent times, scientific studies have been revealing, in today’s terms, about many of the healing and protective properties of curcumin. Curcumin can: • decrease lipid peroxides, thereby limiting damage to mitochondrial membranes • block ROS production • protect neuronal mitochondria in diabetics. (Kazazis et al. 2014)

People considered to be at high risk of developing diabetes can significantly lower their chances of the disease progressing if they supplement or eat curcumin. A 2012 study found that pre-diabetic patients supplementing with curcumin for nine months not only

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reduced their risk of progressing to full type 2 diabetes, but also saw improvements of function in their pancreatic β-cells (Chuengsamarn et al. 2012). In common with many other polyphenols, curcumin has some degree of pro-oxidant activity. However, curcumin does have an extremely good safety record, with multiple gram doses well tolerated (Gupta et al. 2013). Type 2 diabetes and insulin resistance are essentially inflammatory diseases induced by poor diet and lifestyle choices. As an antiinflammatory agent, curcumin can help reduce diabetes-associated inflammation. In a laboratory study, curcumin was found to suppress the formation of adipose tissue and increase the burning of fat through β-oxidation (Kim et al. 2016). These attributes of curcumin are likely to be of benefit to diabetes patients, as they have dysfunctional mitochondria within their adipose tissue. Mitochondrial dysfunction lessens an individual’s ability to metabolize fat through β-oxidation (Sivitz & Yorek 2010). Soluble fibre

A diet high in soluble fibre provides a valuable food source for gastrointestinal bacteria. This allows the microbiota to synthesize the short-chain fatty acids butyrate and propionate. Short-chain fatty acids (SCFAs) are the preferred fuel for the cells that line the colonic epithelium of the large intestine. Seventy per cent of ATP in the colonic epithelium is produced by β-oxidation of SCFAs by epithelial mitochondria (Bourassa et al. 2016; see Chapter 3, ‘Energy Production’). Thus the coloncytes remain healthy by their mitochondria using SCFAs (from soluble fibre) to produce ATP. Additionally, soluble fibre delays gastric emptying, thereby reducing post-mealtime spikes in blood glucose (De Vadder et al. 2014). At a more subtle level butyrate and propionate initiate intestinal gluconeogenesis, an important mechanism for weight and glucose control and regulation. Gluconeogenesis is a mitochondria-dependent process (De Vadder et al. 2014).

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Cinnamon

Cinnamon is a spice long known for its anti-diabetic properties. Cinnamon has been found to reduce oxidative stress and inflammation and to help improve insulin sensitivity in diabetic patients (Tangvarasittichai et al. 2015). It can potentially support brain mitochondria in diabetic patients. In a laboratory study of diabetic animal models, cinnamon supplementation led to a 30 per cent recovery of dysfunctional brain mitochondria (Couturier et al. 2016). Nicotinamide riboside

Nicotinamide riboside is the precursor to NAD+. The anti-ageing protein SIRT1 is dependent on NAD+. Excess calories lead to NAD+ being depleted as it is converted to NADH (see Chapter 6, ‘Acetyl-CoA’), and do not allow SIRT1 to help slow down the ageing process. In a similar way, calorie restriction and exercise will lower energy and raise NAD+, helping to increase the anti-ageing effects of SIRT1. In animal models of diabetes, SIRT1 activation improved glucose regulation and insulin sensitivity in the liver, muscle and adipose tissue (Milne et al. 2007). Activation of SIRT1 is incredibly important for mitochondrial health and efficiency. SIRT1 is an important trigger for mitochondrial biogenesis, that is, the manufacture of brand-new mitochondria (Cantó et al. 2015). Resveratrol

Like NAD+, resveratrol is also an activator of SIRT1. Resveratrol is reported to decrease insulin resistance, support β-cell function and insulin release, and help maintain glucose balance (Szkudelski & Szkudelska 2015). These actions are thought to occur through SIRT1‑related mechanisms. Resveratrol has antioxidant actions which are also protective against diabetes. As with other plant phenols, resveratrol’s antioxidant actions are indirect and occur via the activation of a transcription factor called Nrf2 and genes associated with the antioxidant response element (ARE).

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Antioxidant response element (ARE): a segment of DNA which is activated by oxidative stress and many plant chemicals including resveratrol. Once activated, it enables the production of multiple antioxidant enzymes.

The antioxidant response element helps trigger the expression of many endogenous antioxidant compounds – most of which support mitochondrial function. Curcumin, epigallocatechin gallate (green tea), cinnamic aldehyde (cinnamon) and sulforaphane (broccoli) are all plant compounds that act as indirect antioxidants by activating Nrf2, in a similar way to resveratrol. These compounds have been shown to also have beneficial effects with regard to diabetic complications (Bhakkiyalakshmi et al. 2015). Vitamin D

Vitamin D has the ability to help normalize glycaemic control, insulin resistance and inflammation. Vitamin D has helped slow or halt pre‑diabetic patients’ progression to full type 2 diabetes (Dutta et al. 2014). Vitamin D metabolism depends on cytochrome enzymes found largely  within liver and kidney mitochondria. The first step is the conversion of vitamin D to 25OHD, which is shared between mitochondria and the endoplasmic reticulum, and the second step is the conversion of this 25OHD to 1,25(OH)2D, the active form of vitamin D, which occurs mainly in kidney mitochondria. Clearance of vitamin D is carried out by another mitochondrial cytochrome enzyme (Bikle 2014). Thus healthy mitochondria are required for vitamin D utilization. Taurine

The antioxidant potential of taurine makes it protective against diabetic complications and mitochondrial dysfunction. Taurine also works with uridine to support the genetic translation of proteins involved in the mitochondrial electron transport chain (see Chapter 3, ‘Energy Production’, and Ito et al. 2012).

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β-Glucans

Although research is still in its early stages, the insulin-sensitizing and glucose-stabilizing ability of β-glucans may be in part due to their positive effect on mitochondria. β-Glucans have been found to increase the expression of mitochondrial SOD (superoxide dismutase) (Agostini et al. 2015), an antioxidant enzyme associated with decreased muscle insulin resistance in laboratory animals (Boden et al. 2012). β-Glucans have also been found to increase the expression of a protein called Parkin in blood vessels (Casieri et al. 2017). Underexpression of Parkin may lead to mitochondrial dysfunction and muscle insulin resistance – effectively associating poor-quality mitochondria with insulin resistance (Montgomery & Turner 2015). Mitochondria are involved in insulin resistance and type 2 diabetes via their roles in insulin synthesis in pancreatic beta cells, and insulin sensitivity within target cells. Nutrition can support both beta cell and target cell mitochondria to produce and regulate insulin activity.

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19 Hypertension

The control of blood pressure is dependent on the balance between dilation and constriction of the blood vessels, through mechanisms within the vascular endothelium (blood vessel lining). The opposing actions of two free radicals, the oxygen radical superoxide and the nitrogen radical nitric oxide, work to maintain our appropriate blood pressure. Angiotensin II and endothelin are two compounds that mediate vasoconstriction (constriction of the blood vessels) and do so by activating NADPH oxidase (NOX). NOX is an enzyme that produces superoxide to antagonize endothelial nitric oxide synthase (eNOS) in the vascular endothelium (Pollock 2005).

eNOS: vasodilator – reduces blood pressure. NOX: vasoconstrictor – increases blood pressure.

When in balance, correct blood pressure is maintained, but excessive superoxide production by NOX can overwhelm eNOS, leading to

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hypertension and vascular dysfunction. In the long term, vascular dysfunction can set in motion changes in the blood vessel walls that could eventually result in atherosclerosis, aneurysm, stroke and vascular dementia (Dikalov & Ungvari 2013). It’s not only NOX that produces superoxide. Dysfunctional mitochondria are major producers of this free radical. Mitochondria can therefore increase the superoxide load and shift a blood vessel toward vasoconstriction. Alternatively, mitochondria also have the ability to quench superoxide (via mitochondrial superoxide dismutase and glutathione peroxidase), thereby protecting against hypertension (Dikalov & Ungvari 2013). Smoking and lack of exercise are two potential reasons for an increase in mitochondrial reactive oxygen species (ROS) in the cells of blood vessels. Another reason is that there is a decrease in the action of mitochondrial superoxide dismutase as we age. By the time a person reaches 65, the anti-ageing SIRT proteins in mitochondria have lost 40 per cent of their activity. Excessive acetyl-CoA can acetylate and inhibit mitochondrial superoxide dismutase (Dikalov & Dikalova 2016). High-fat and high-starch diets, excessive calorie diets and alcohol all increase mitochondrial acetyl-CoA and could potentially inhibit mitochondrial superoxide dismutase. Xanthine oxidase is an enzyme that metabolizes purine nucleotides to uric acid, a compound which, in excess, can lead to gout. High xanthine oxidase activity can increase the production of mitochondrial ROS, leading to ‘dysfunctional’ diastolic blood pressure (Vergeade et  al. 2012). Although diets which are high in purines (e.g. seafood and meat) could potentially raise the activity of xanthine oxidase, it is usually other factors which increase the enzyme’s activity. Oxidative stress, inflammation and high body mass index are all risk factors (Feoli et al. 2014). The enzyme eNOS (which enables vasodilation) requires insulin for its function. Therefore, insulin resistance will undermine its ability to dilate blood vessels (Muniyappa & Sowers 2013). Please read Chapter 18, ‘Insulin Resistance and Type 2 Diabetes’, for a greater insight into the relationship between mitochondria and insulin resistance.

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Key mitochondrial nutrients to support the reduction of mitochondrial ROS and the increase of vasodilation In moderation mitochondrial ROS can be beneficial to health through their support of hormesis and fighting infection. In excess, mitochondrial ROS are generally detrimental to health. Blood vessels are particularly sensitive to the damaging effects of mitochondrial ROS. The nutrients below can also assist the correct functioning of the enzyme eNOS, the enzyme that dilates blood vessels. Coenzyme Q10 (CoQ10)

CoQ10 is a vital compound which operates within the electron transport chain of mitochondria – including blood vessel endothelial mitochondria. Without CoQ10, endothelial mitochondria produce an increasing amount of ROS, which raises the risk of hypertension (Dikalov & Dikalova 2016). In animal models, supplementation of CoQ10 was able to reduce blood pressure in hypertensive animals (Gladwin et al. 2005). Plant polyphenols

Epigallocatechin-3-gallate or EGCG (from green tea), resveratrol (from grapes and Japanese knotweed), ginkgo biloba and oligomeric proanthocyanidins (OPCs) (from bilberry and grape extracts) have all been found to help lower diastolic blood pressure in hypertensive patients (Biesinger et al. 2016). The citrus bioflavonoid naringenin has been observed to protect against hypertension and to re-sensitize cells to insulin (Sumathi et al. 2015). (Note that naringenin is contraindicated with many medications.) Earlier we saw that these phytochemicals reduce mitochondrial ROS by activating our own antioxidant enzymes, through their action of causing stress to the body. Folate and vitamin C

eNOS (the enzyme that dilates blood vessels) depends on a little-known nutrient called biopterin, a compound related to folate and riboflavin. Serotonin, dopamine, adrenaline and noradrenaline also depend on biopterin for their own synthesis. 171

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Biopterin is not readily available as a supplement, as it is not a particularly stable compound. A far better approach is to support its activity and stability with folate and vitamin C. With biopterin more stable, the whole eNOS enzyme becomes more stable. Folate can help restore the function of eNOS in patients with atherosclerosis, diabetes and high cholesterol (Kietadisorn et al. 2011). Vitamin C can also assist by stabilizing eNOS and maintaining its activity for several hours (Ladurner et al. 2012). Chapter 15, ‘Health, Toxicity and Hormesis’, referred to how vitamin C supplementation may undermine the health benefits of exercise-induced ROS in healthy people. When a patient is displaying overt health issues, then they are no longer in the ‘hormesis zone’ for their condition. When this occurs, the research supports the use of antioxidants such as vitamin C. Frustratingly, eNOS has the ability to synthesize not just nitric oxide, but also hypertensive superoxide. eNOS produces nitric oxide to help maintain normal blood pressure, but, when this process is disrupted or uncoupled,8 it can produce damaging levels of superoxide (Kietadisorn et al. 2011). It is therefore essential to support eNOS and protect against its dysfunction. eNOS can be supported by exercise, folate and vitamin C, improving insulin sensitivity and reducing inflammation and oxidative stress. eNOS produces much lower levels of nitric oxide compared to iNOS (inducible nitric oxide synthase), the enzyme induced by the immune system. eNOS and its product nitric oxide are vital for the function of blood vessels. The larger levels of nitric oxide produced from iNOS are designed to damage and destroy pathogens, but can damage mitochondria and other tissue in the process. Failure to support eNOS also puts a person at risk of hypertension and cardiovascular disease. Although the mechanism is not completely understood, mitochondria also have a need for biopterin. Researchers have found that loss of mitochondrial biopterin can lead to increased mitochondrial superoxide and lowered glutathione in the vascular endothelium 8 Through deficiency or damage to the co-factor biopterin, insulin resistance (the enzyme is also activated by insulin), lack of the amino acid arginine (precursor to nitric oxide) (Li & Förstermann 2017) xanthine oxidase and mitochondrial ROS (Kietadisorn et al. 2011).

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(Bailey et al. 2017). In theory, folate and vitamin C should be able to support mitochondrial biopterin in the same way that they support biopterin in eNOS. Folate supports mitochondria in yet another way. Mitochondrial DNA is stabilized by folate, and this action becomes even more important when mitochondrial DNA is damaged in mitochondrial disorders (Ormazabal et al. 2015). The need for, and dosage of, folate and vitamin C can be determined by laboratory tests of urinary organic acid, amino acid and blood markers of aspects of methylation and oxidative stress. Homocysteine is another useful test to help indicate folate need, particularly as homocysteine is linked with eNOS uncoupling (Kietadisorn et al. 2011). Pomegranate

For the vascular endothelium to relax in response to increased blood flow, eNOS has to respond to something called ‘shear stress’. Shear stress is induced when the greater flow of blood from exercise puts pressure on blood vessel walls. One benefit of exercise is that the increased shear stress on blood vessel walls leads to a greater expression of the cardioprotective enzyme eNOS. ROS and cardiovascular disease can make the vascular endothelium less sensitive to shear stress, but pomegranates (rich in the polyphenol punicalagin) can help restore blood vessel responsiveness to shear stress (de Nigris et al. 2007). Mitochondria within the vascular endothelium are primed to respond to shear stress by increasing their numbers. A benefit of shear stress is that it can improve mitochondrial integrity in vascular cells, resulting in the reduction of damaging ROS in blood vessel walls (B. Kim et al. 2014). Taurine

The amino acid taurine has anti-hypertensive properties. Surprisingly, one of the main anti-hypertensive actions of taurine is to increase the blood levels of the gas hydrogen sulphide (Sun et al. 2016). Hydrogen

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sulphide is the gas associated with the smell of ‘bad eggs’. It is toxic in large amounts, but at smaller levels is highly protective to blood vessels. In diabetes, blood vessels are subjected to increased blood glucose, leading to a rise in mitochondrial ROS in the endothelium. Diabetics have lower levels of blood hydrogen sulphide than normal. It has been found that raising the level of hydrogen sulphide can lead to a reduction in mitochondrial ROS, thereby protecting the blood vessels of diabetics from glucose toxicity (Módis et al. 2014). Omega-3 fatty acids

The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have hypotensive effects. Fish oils have been found to modestly lower systolic and diastolic blood pressure in many studies, with the best results seen in the elderly and those with hypertension (Cottin et al. 2011). One-off blood pressure measurements do not fully reflect EPA and DHA benefits, with most benefits seen in 24-hour continual blood pressure measurement. This kind of blood pressure measurement is called ambulatory and is more representative of a person’s day-in, day‑out blood pressure (Cottin et al. 2011). DHA is the omega-3 fatty acid that has the most effect on ambulatory blood pressure. To synthesize DHA from EPA, EPA has to undergo β-oxidation in mitochondria (De Caterina & Basta 2001). It would therefore be wise to supplement DHA for hypertension rather than fatty acid precursors, to avoid dependence on mitochondrial β-oxidation. An erythrocyte membrane essential fatty acid profile (available from various labs) can ascertain the need and dosage of DHA. (Ironically, both EPA and DHA can help stimulate β-oxidation, once they are both supplemented (Cottin et al. 2011).) Beetroot

Beetroot is a rich source of nitrates which can be transformed (via nitrites) into a useful source of nitric oxide to support blood vessel health. Many studies have shown that a diet supplemented with beetroot juice results in a favourable reduction in systolic blood pressure (Siervo et al. 2013). eNOS is not used to provide nitric oxide from beetroot, making this source of nitric oxide very helpful for those with hypertension due 174

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to eNOS dysfuncton. Interestingly, mitochondria provide one of the sites for the conversion of nitrites to nitric oxide (Dungel et al. 2017).

Salt – good or bad for hypertension? If you have managed to get this far into the book, you’ll now realize that many health issues are not quite as simple as they seem. Stand close to an Old Master painting in an art gallery and you will only see the confusing brush strokes – stand back and all the complex strokes come together to give meaning to the masterpiece. The often-espoused mantra of maintaining a low-sodium diet to prevent high blood pressure is drummed into us all by many health professionals. However, like everything, it’s the person, the context, genetics, lifestyle and environment that determine how to proceed with health decisions. The one-size-fits-all mantra of a low-sodium diet may even be dangerous for many healthy individuals. A low-salt diet can increase insulin resistance, blood lipids and low-intensity lipoprotein (LDL) cholesterol, and even increase the risk of heart failure (Adams et al. 2005; Graudal et al. 1998; Kalogeropoulos et al. 2015). Therefore, strict adherence to a low-sodium diet could predispose a healthy person to the very conditions that they are trying to prevent! This is not to say that we should all go out and recklessly smother our food in salt! There is plenty of evidence that excessive salt intake is harmful. However, just because something is harmful in excess, or to a vulnerable sub-population, doesn’t mean every single person has to adopt a strict low-sodium diet. A clue to what happens when a person adopts a strict low-sodium diet is found in how the body responds to low sodium. In a way, a strict low-sodium diet creates a hypotensive crisis which then initiates an emergency reaction to raise blood pressure. Low-sodium diets activate both the sympathetic nervous system and the renin–angiotensin system, forcing the body to raise blood pressure (Stolarz-Skrzypek et al. 2011). Worryingly, angiotensin II raises blood pressure by triggering the production of the damaging radical superoxide in blood vessels (Welch 2008). 175

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THE RENIN–ANGIOTENSIN SYSTEM The renin–angiotensin system is a mechanism that assists in the control of blood pressure. The kidneys are the initial sensors of blood pressure changes in this system. Drugs called ACE (angiotensinconverting enzyme) inhibitors block the hypertensive effects of the renin–angiotensin system.

Overall, the evidence seems to suggest avoiding excessive sodium intake, but not avoiding sodium totally. A sodium deficiency triggered by a strict low-sodium diet may induce a compensatory reaction in blood vessels which could potentially be far more harmful than the risks of sodium in the diet. For example, diets which contain over 2300mg of sodium per day have been found to mildly increase the risk of all-cause mortality in elderly patients. However, low-sodium diets containing under 1500mg of sodium per day can also increase the risk of all-cause mortality in elderly patients (Kalogeropoulos et al. 2015).

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The heart depends on mitochondria for 95 per cent of its adenosine triphosphate (ATP) (the remaining 5% coming from glycolysis) and, along with the brain, is the organ with the highest energy demand for the whole of the human body (Ussher 2014). Astonishingly, every day cardiac mitochondria have to synthesize 6kg of ATP to meet the heart’s energy requirements for contraction (Murray 2011). A heart muscle cell, or cardiomyocyte, can contain around 6000 mitochondria, which constitute between 20 and 40 per cent of the cell volume (X. Huang et al. 2013). The heart pumps five litres of blood every minute at rest, and this increases to an amazing 25 litres per minute during exercise. The huge demands on the heart mean that a brand-new heart is reconstructed from proteins, fats and carbohydrates every 30 days (Valiyakizha Kkeveetil et al. 2016). This allows the heart to remain at peak efficiency to maintain its vital life-giving functions. β-Oxidation of fatty acids is the preferred method of producing cardiac energy, providing between 60 and 80 per cent of mitochondrial ATP (see Chapter 3, ‘Energy Production’). However, incorrect or incomplete β-oxidation within the heart has been associated with heart failure, ischaemic heart disease and diabetic cardiomyopathy (Ussher 2014). 177

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Calcium and the heart Calcium is a vital mineral for cardiac function. Mitochondria are master controllers of calcium waves, as we’ve seen in Part 1, and these help to optimize muscle contractions in the heart. Mitochondrial control of calcium waves can conserve cardiac energy by dampening excessive heart muscle contraction. Mitochondrial sensitivity to calcium makes mitochondria ideal for matching ATP output to increased cardiac workload. Dysfunctional mitochondria in cardiomyocytes may lead to excessive calcium release from cellular stores, resulting in cardiac arrhythmias (Miragoli et al. 2016). In turn, calcium leakage from cellular stores (the sarcoplasmic reticulum in cardiomyocytes) can overwhelm mitochondria and trigger further mitochondrial dysfunction (Santulli et al. 2015). Some of the key causes of mitochondrial dysfunction in cardiomyocytes are insulin resistance, calcium overload, oxidative stress and increased β-oxidation leading to toxic fat accumulation (lipotoxicity). Exacerbating mitochondrial dysfunction, ageing and diseased cardiomyocytes perform far less mitochondrial biogenesis to create brand-new mitochondria (Rosca & Hoppel 2013).

Insulin resistance and the heart Insulin resistance within the heart is problematic, even though the heart relies mainly on β-oxidation of fatty acids for its energy supply. Ideally fat uptake into cardiomyocytes should be matched to appropriate β-oxidation, as poor β-oxidation may lead to incomplete fat oxidation, with fatty acid by-products hindering insulin signalling. Excessive glucose intake can also lead to insulin-resistance, and antagonizes β-oxidation of fats (Zhang et al. 2010). Although insulin resistance is a driver for many cardiac health conditions, insulin resistance may initially be a protective strategy to help reduce the damaging effects of over-nutrition on cardiomyocytes. It is therefore important to ensure that insulin-resistant cells are safe from macronutrient excess to reduce the chances of mitochondrial overload and reactive oxygen species (ROS) production (Taegtmeyer 178

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et al. 2013) – before making them more sensitive to insulin. Dietary improvements are the safest way of achieving this as the improvements will occur side‑by-side with increases in insulin sensitivity. It is potentially damaging to use a supplement to increase insulin sensitivity whilst continuing a diet with macronutrient excess.

Mitochondria and the heart Damaged fats called lipid peroxides can be harmful to the heart. The mitochondrial enzyme ALDH2 provides one route for the clearance of lipid peroxides (Guo et al. 2013), and mitochondrial β-oxidation provides another route. This means that, if cardiac mitochondria are dysfunctional, lipid peroxides may accumulate and compromise the heart. In addition, insulin resistance, obesity and type 2 diabetes may all undermine β-oxidation and therefore lipid peroxide detoxification (Li et al. 2013). Mitochondria are thought to be both the source and target of many damaging lipid peroxides, but strangely, in very low amounts, they may be protective. Just like many plant polyphenols, lipid peroxides activate the body’s own antioxidant defence system. The transcription factor Nrf2 senses lipid peroxides and activates the antioxidant response element (ARE) within our DNA. The result is to increase the endogenous production of glutathione and other essential antioxidants. The activation of the antioxidant defence systems by small amounts of lipid peroxides is a process called hormesis. This is where a small amount of toxin elicits a larger beneficial response. Exercise is another example of hormesis; short-term increases in ROS during exercise provide a long-term benefit to the body as a whole (Anderson et al. 2012). Please read Chapter 15, ‘Health, Toxicity and Hormesis’, for more information.

Kissing and nanotunnels to heal cardiac mitochondria Unlike many cells, cardiomyocytes (heart muscle cells) contain mitochondria that are not motile (mobile). In neurons, mitochondria 179

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are transported on cytoskeletal tracks, up and down the relatively long distances along an axon. In cardiomyocytes, mitochondria form static networks of around 6000 individual mitochondrion (X. Huang et al. 2013). Static cardiac mitochondria all work together as a team, supporting each other to maintain their essential ATP-producing output. If a mitochondrion in close proximity to another requires assistance, it is literally ‘kissed’ so that reparative contents can be exchanged (X. Huang et al. 2013). At longer distances in the cardiomyocyte, mitochondria use ‘nanotunnels’ to interconnect. Nanotunnels are like hose pipes where contents and information can be exchanged between non-adjacent mitochondria (Huang et al. 2013b). Stem cell researchers have opened up an exciting new area of research related to repairing damaged or dysfunctional cardiomyocytes. In their research they have discovered that introduction of stem cells to a damaged heart can lead to a miraculous recovery in damaged cardiac cells. In a similar way to mitochondria forming nanotunnels within a cardiomyocyte, stem cells form tunnelling nanotubes (TNTs) outside a cardiac cell. Stem cell tunnelling nanotubes burrow through a cardiac cell wall, to allow the injection of brand-new mitochondria (Rodriguez & Mahrouf-Yorgov 2016) – literally a change of batteries to revive an ailing cardiomyocyte!

Key mitochondrial nutrients to support the heart Magnesium

The heart synthesizes 6kg of ATP every day (Murray 2011), and 95 per cent of this is derived from mitochondria (Ussher 2014). Every molecule of adenosine diphosphate (ADP) needs to be complexed with a magnesium ion. In truth, ATP is really magnesium-ATP or MgATP, and, without sufficient magnesium, a phosphate ion cannot bind correctly to adenosine diphosphate (ADP) to make ATP in mitochondria (Blum et al. 2012).

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Mitochondrial dysfunction has been implicated in cardiac arrhythmias where reduced ATP synthesis and increased ROS production can lead to imbalances in electrical currents within the heart (Yang et al. 2014). Magnesium can be used to treat many types of cardiac arrhythmia (Ho 2008). In the section ‘Calcium and the heart’ above, calcium was discussed as being both essential for cardiac function, yet also problematic in a  diseased heart. Magnesium helps to protect an ageing heart as it is a natural calcium antagonist. Magnesium works with calcium to maintain the integrity and function of cardiac muscle cells (Gröber et al. 2015). ATPases are enzymes which enable ion transfers across membranes. In cardiac cells, a major ATPase is the sarcoplasmic reticulum calcium, magnesium ATPase. Mitochondria remain in close proximity to ATPases to provide the high levels of ATP required to power these vital enzymes (Seppet et al. 2001). The contractions of cardiac muscle require ATPases to co-ordinate calcium flow within the heart – again, with the assistance of magnesium and mitochondria. Taurine

The name ‘taurine’ is derived from ‘taurus’, the Latin word for ‘bull’, as taurine was first discovered in the bile of oxen. A quarter of the amino acid pool within cardiomyocytes is comprised of taurine. As a free amino acid, taurine is not used as a building block for protein synthesis, but rather is used as an important calcium regulator and antioxidant (Soukoulis et al. 2009). Taurine is often called a ‘non-essential amino acid’ because it is not a structural amino acid in protein. However, this is a misnomer since taurine is far from non-essential in the heart. As well as the heart, high levels of taurine are maintained in the spinal cord, retina, brain and white blood cells (Ripps & Shen 2012). Like mitochondria, taurine protects cardiomyocytes from calcium overload (Soukoulis et al. 2009), and taurine can even help mitochondria regulate their own calcium load (El Idrissi & Trenkner 2003). Taurine levels are often reduced in failing human hearts and in animal models of heart disease (Soukoulis et al. 2009).

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Hawthorn fruit extracts (Crataegus)

For many years, hawthorn berries have been traditionally used by herbalists to treat arrhythmias, increase blood flow to the heart, and improve the contractions of heart muscle. Mitochondrial dysfunction has been found to be implicated in all of these cardiac conditions. Hawthorn berry phenol compounds have been shown to be supportive of cardiac mitochondria in vitro (Bernatoniene et al. 2009). Hawthorn phenols can preserve cardiac antioxidants and help prevent mitochondrial lipid peroxidation in laboratory animals (J. Wang et al. 2013). Coenzyme Q10 (CoQ10)

CoQ10 acts as a carrier for electrons in the electron transport chain and it therefore plays an essential role in ATP synthesis. CoQ10 is especially important in the heart, due to the high energy demands of cardiomyocytes. CoQ10 synthesis is dependent on HMG-CoA reductase, the enzyme that is inhibited by cholesterol-reducing statin drugs. It may be wise to supplement CoQ10 if a cardiovascular patient is prescribed a statin, to help preserve full ATP production in mitochondria. Although CoQ10 has been found to be deficient in heart failure patients, frustratingly there hasn’t been sufficient good-quality research into its supplementation. Many small-scale studies do show promising results, but there are just as many studies showing no or little effect. In defence of CoQ10, these inconclusive studies often gave low doses of CoQ10 or supplemented for a short period of time (Soukoulis et al. 2009). Studies looking at supplementing 120mg/day of CoQ10 for 48 to 72  hours after non-fatal myocardial infarction have shown more promising results. In these studies, there were reductions in arrhythmias, angina and other cardiac events. Cardiac benefits were still apparent up to a year after the initial infarction (Martinez & Rollins 2016). There is an ongoing debate regarding the most beneficial form of CoQ10 to take. The oxidized form of CoQ10 is ubiquinone, and the reduced active form is ubiquinol. There are some suggestions that CoQ10 in cardiovascular research should be repeated with ubiquinol,

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as this is considered by many to be a superior form of the supplement (Cohen 2015). Indeed it seems likely, from animal research, that more ubiquinol reaches the desired mitochondrial destination than ubiquinone (García-Corzo et al. 2014). Ubiquinone and ubiquinol are both antioxidants in addition to their activity in the mitochondrial electron transport chain. Ubiquinone is the more effective superoxide radical scavenger, and ubiquinol is the more effective scavenger of lipid peroxides (Maroz et al. 2009). Ubiquinol may be more effective at protecting low-density lipoprotein (LDL) cholesterol from lipid peroxides than vitamin E (Cervellati & Greco 2016). Mitoquinone (a mitochondrial-targeted antioxidant and CoQ10 analogue) has been modified by the addition of a phosphonium ion. This addition allows it to cross mitochondrial membranes more easily than natural CoQ10 formulations. Once inside a mitochondrion, mitoquinone acts purely as an antioxidant, having no involvement in electron carrying in the electron transport chain. In animal models of cardiovascular disease, mitoquinone is showing a lot of promise. After supplementing it, improvements have been seen in blood pressure, and cardiac and vascular integrity (Graham et al. 2009). What is often overlooked in much of the research is the interrelationship of antioxidants. In reality, CoQ10 cannot work alone as an antioxidant – it forms part of an antioxidant system where vitamin E, vitamin C, glutathione, lipoic acid and CoQ10 all work together to provide an extremely powerful radical fighting team (Sen & Packer 2000). Carnitine

Carnitine is a cardio-protective compound synthesized from the amino acid lysine. During carnitine’s synthesis, lysine is methylated three times, requiring the amino acid methionine as a methyl donor. Carnitine assists the transport of fatty acids into mitochondria – an absolutely essential role, considering how dependent heart mitochondria are on fatty acids for energy. Carnitine can also aid carbohydrate metabolism by supporting the activity of the pyruvate dehydrogenase complex – the enzyme complex which allows pyruvate from glycolysis to

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enter the tricarboxylic acid (TCA) cycle of mitochondria (see Chapter 3, ‘Energy Production’). Heart failure patients have been reported to suffer from carnitine deficiency, and supplementation of carnitine has led to improvements in exercise capability, heart rate and oxygen usage in heart failure patients. In studies with cardiac patients, the most effective form of carnitine for absorption into cardiomyocytes may be propionyl-Lcarnitine (Soukoulis et al. 2009). Thiamine

Thiamine deficiency is surprisingly common in heart failure patients. Like carnitine, thiamine supports the activity of the pyruvate dehydrogenase complex. This highlights just how important this complex is in heart health – and the vital role mitochondria play in maintaining heart energy. Many small-scale studies with heart failure patients have found that thiamine supplementation may improve heart function and reduce symptoms. Thiamine deficiency can be induced by the use of diuretics and lower absorption as a person ages (Jain et al. 2015). The elderly may also fall into the habit of choosing less nutrient-dense foods as these are often more convenient to prepare. It’s not just thiamine deficiency that can be problematic in heart conditions – all B vitamins are needed to maintain a healthy heart. In fact the likelihood of heart failure patients having a B vitamin deficiency is as high as 68 per cent (Soukoulis et al. 2009).

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21 Cholesterol Metabolism

Cholesterol is a much-maligned molecule that is essential for the survival of all cells. Cell membranes and intracellular lipids contain cholesterol to help keep their structure, fluidity and integrity. Steroid hormones, vitamin D and bile acids are all reliant on cholesterol for their synthesis. Cholesterol, like a mitochondrion, has a shelf life and can cause health  problems if it is not recycled before the end of its useful life. The labels of ‘bad’ cholesterol for low-density lipoprotein (LDL) cholesterol  and ‘good’ cholesterol for high-density lipoprotein (HDL) cholesterol are generally not that helpful. Out-of-range levels of LDL-C (LDL cholesterol) and HDL-C (HDL cholesterol) should really only be used as indicators of deeper metabolic issues, and not as ends in themselves. Damaged cholesterol and a disordered cholesterol metabolism can be particularly problematic in cardiovascular health. The presence of oxidized LDL in blood vessels is a driver for inflammatory macrophages to infiltrate the vascular wall to mop up damaged cholesterol. Macrophages engorged with cholesterol become the foam cells at the core of atherosclerotic plaque (Ravi et al. 2014).

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Foam cells: formed from macrophages of the immune system that have entered the blood vessel wall. When loaded with cholesterol they develop the ‘foamy’ appearance that gives them their name.

Mitochondria, the starting point for cholesterol synthesis Mitochondria play several roles in both healthy and aberrant cholesterol metabolism. Cholesterol synthesis and regulation, protection of cholesterol from oxidation, foam cell formation and LDL particle size are all issues that have a relationship with mitochondria. Mitochondrial citrate export is the starting point for cholesterol synthesis, just as it is for saturated fatty acid synthesis (see Chapter 7, ‘Synthesizing Cellular Components’). Citrate is exported via the mitochondrial citrate carrier and then converted to acetyl-CoA in the cytosol, to begin cholesterol synthesis (Ferramosca & Zara 2014a). Mitochondrial dysfunction may negatively impact the regulation of cholesterol synthesis through the mitochondrion’s role in inducing insulin resistance (see Chapter 18, ‘Insulin Resistance and Type 2 Diabetes’). The following section explores how insulin resistance can lead to excess cholesterol synthesis.

How insulin resistance can lead to raised cholesterol and raised atherogenic LDL-C SREBP-2 (sterol regulatory element-binding protein 2) is a protein that controls cholesterol synthesis and should become inactive in the presence of cholesterol. This normally provides a neat feedback mechanism to inhibit excess cholesterol synthesis (Van Rooyen & Farrell 2011). Insulin resistance, however, can lead to SREBP-2 becoming insensitive to the inhibitory effects of cholesterol. With the loss of control of SREBP, the enzyme HMG-CoA reductase (the rate-limiting

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enzyme for cholesterol synthesis) is likely to over-produce cholesterol (Van Rooyen & Farrell 2011). Additionally, lipoprotein lipase activity is undermined by insulin resistance, leading to LDL-C particles becoming small and dense (sdLDL). It is interesting that sdLDL levels are also a good marker for insulin resistance and pathogenic alterations in arterial wall thickness (Gerber et al. 2013; Toth 2014).

Mitochondria can support the clearance of cholesterol products As mentioned above, macrophages engorged with oxidized cholesterol become foam cells within blood vessel walls. However, the behaviour of macrophages is dramatically different depending on their energy metabolism. Glycolytic macrophages are called M1 macrophages and are highly inflammatory. Anti-inflammatory M2 macrophages rely on mitochondrial oxidative phosphorylation and can help clear oxLDL (oxidized LDL) and resolve arterial inflammation (Ravi et al. 2014). The polarization of macrophages to either M1 or M2 depends on the type  of cytokines surrounding macrophages and the presence or absence of bacterial infection. Inflammatory cytokines and bacterial infection favour M1 expression. Anti-inflammatory cytokines favour M2 expression. Diet and lifestyle can also influence M1/M2 polarization. In laboratory animals, obesity led to a shift in type to M1 macrophages and exercise to M2 macrophages (Chinetti-Gbaguidi & Staels 2011). LDL-C is vulnerable to oxidation in the presence of lipid peroxide aldehydes such as 4-hydroxy-2-nonenal (4-HNE), hydroxyhexenal (HHE) and malondialdehyde (MDA), which all come from the lipid peroxidation of polyunsaturated fatty acids (Albert et al. 2013; Ayala et al. 2014). In turn, oxLDL-C also has the ability to damage fats and generate lipid peroxides (Liu et al. 2015; Leonarduzzi et al. 2005). Mitochondria contain an aldehyde detoxifying enzyme called ALDH2 that plays a vital role in clearing these toxic aldehydes (Guo et al. 2013). A specific type of oxidized cholesterol (synthesized in the mitochondria) can be beneficial. Mitochondria oxidize cholesterol to

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produce 27-hydroxycholesterol, an oxysterol which activates genes involved in cholesterol export or efflux from macrophages. This mitochondrial-dependent cholesterol efflux is thought to help prevent foam cell formation, which, left unchecked, could eventually lead to atherosclerosis (Allen et al. 2013). However, raised circulating cholesterol can cause excess mitochondrial-derived 27-hydroxycholesterol. This excess can exert detrimental effects on many organs and tissue. For example, 27-hydroxycholesterol can act as an agonist of oestrogen receptors and has been associated with breast cancer risk and progression (Lee et al. 2014). 27-Hydroxycholesterol is an endogenous oxysterol, but there are also concerns about dietary oxysterols. Dietary oxysterols (from the foods listed below) have been linked with conditions such as cardiovascular disease, neurodegenerative disease, inflammatory bowel disease and retinal degeneration (Poli et al. 2013). Oxysterols can be damaging to mitochondria by inhibiting mitochondrial biogenesis and impairing respiration – both resulting in mitochondrial dysfunction (Bellanti et al. 2014).

Food processing and storage can lead to the formation of toxic oxysterols Although animal produce does contain oxysterols, the vast majority of these highly toxic compounds occur through poor food storage and processing. Reducing our cholesterol intake is meaningless if the cholesterol we do consume is riddled with oxysterols. Partially cooked cholesterol-containing foods will continue to degrade their cholesterol into oxysterols – even if chilled or frozen. Cholesterol exposed to air and light will degrade to oxysterols. For example, pre-grated cheese and processed egg powder contain substantially more oxysterols than fresh cheese or eggs. To tar fresh cholesterol-containing foods with the same brush as processed cholesterol foods is extremely foolhardy!

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Studies examining the content of toxic oxysterols in eggs (e.g. Savage et al. 2002) found 311µg oxysterol per gram of lipid in whole egg powder – in fresh eggs, no oxysterols were found.

Cholesterol – not all bad! It must be remembered that cholesterol is a vital biochemical compound which is essential for the life of animals – and that includes humans! The problem with cholesterol is its vulnerability – like mitochondria, it has a shelf life and needs to be synthesized, used and then removed in the most efficient way possible. As we age, it becomes even more important to ensure a healthy cholesterol metabolism. In fact in the elderly, lower cholesterol has been found to increase the chances of mortality, rather than reducing mortality (Schatz et al. 2001). It’s hard to understand how society has become so fixated with cholesterol. If mitochondria become dysfunctional, we do not try to eliminate all mitochondria – we try to improve their function. Cholesterol should be treated the same way – we should be focused on maintaining cholesterol’s integrity and function, not just blindly keeping levels low.

Key mitochondrial nutrients to help support healthy cholesterol metabolism Plant polyphenols

Plant polyphenols provide many benefits for atherosclerosis prevention and are extremely protective at many levels of cholesterol metabolism. Berries, nuts, cocoa, grapes, pomegranate, sage, coffee and tea contain a host of highly beneficial polyphenols (Park et al. 2012; Zanotti et al. 2015). As we’ve seen above, in atherosclerosis, macrophages of the immune system infiltrate the vascular endothelium, become engorged with

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modified LDL-C and form foam cells. Foam cell formation is a major feature of atherosclerotic plaque. Foam cells expel cholesterol through a process called cholesterol efflux – efflux is dependent on mitochondrial adenosine triphosphate (ATP) to drive transporters called ATP-binding cassettes. Loss of mitochondrial ATP in foam cells can lead to an increasing build-up of cholesterol and a worsening of atherosclerosis (Karunakaran et al. 2015; Zanotti et al. 2015). Coffee, grapes, walnuts, pomegranate, olive oil, sage and berries are the foods most associated with cholesterol efflux. Coffee may be better if filtered, as the filtering removes diterpene compounds, found to raise cholesterol (Park et al. 2012; Zanotti et al. 2015). In one study, participants drinking 4–6 cups of unfiltered boiled coffee per day over a nine-week period experienced a 0.39 mmol/L increase in LDL-C (Bak & Grobbee 1989). The cholesterol effluxed from a macrophage/foam cell undergoes reverse cholesterol transport back to the liver, carried by an HDL particle. In the laboratory, ginger extract has been found not only to encourage cholesterol efflux, but also to increase HDL-C and mitochondrial biogenesis in skeletal muscle (Oh et al. 2017). Omega-3 fatty acids

The synthesis of cholesterol starts in mitochondria from a molecule of citrate. It’s the export of citrate from mitochondria, rather than entering the TCA (tricarboxylic acid) and electron transport chain, that makes all the difference. Exporting citrate, rather than burning it for energy, leads to an anabolic-type metabolism and helps with cell building. It provides the citrate/acetyl-CoA required for cholesterol and fatty acid synthesis. Please read Chapter 7, ‘Synthesizing Cellular Components’, for more details. So, a good way to reduce cholesterol is to ‘choke off’ the supply of citrate/acetyl-CoA that cholesterol is initially synthesized from. Inhibition of the mitochondrial citrate carrier (CIC) is one way of achieving this (Ferramosca & Zara 2014a). The omega-3 fatty acid DHA (docosahexaenoic acid) is an inhibitor of the mitochondrial citrate carrier (Iacobazzi et al. 2013).

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Cholesterol synthesis is regulated by SREBPs. Through interactions with several nuclear receptors, omega-3 fatty acids have a positive effect on SREBPs, and thus on cholesterol and triglyceride levels (Davidson 2006), and a consequent lowering of cholesterol. Omega-3 oils increase β-oxidation of fatty acids in mitochondria, enabling a shift from lipid storage to fatty acid β-oxidation and energy production (Davidson 2006). Carnosic acid

Carnosic acid is a diterpene found in the herbs rosemary, thyme and sage. Carnosic acid increases the degradation of SREBP. Consequently, lower availability of SREBP leaves DNA unable to express as many cholesterol and lipid synthesis genes (Xie et al. 2017).

Diterpene: are a group of natural compounds with a diverse range of properties. Diterpenes in many herbs are known for their ability to reduce cholesterol synthesis. Diterpenes from coffee may increase cholesterol synthesis. Filtering coffee reduces the diterpenes.

Taurine

Taurine can help lower blood levels of VLDL (very low density lipoprotein) and LDL-C. Although taurine works at many different levels throughout our metabolism, it’s the improvement in efficiency of bile metabolism that is thought to be the main way in which taurine lowers cholesterol. The secretion of bile is the major way cholesterol is removed from the body (Murakami 2014). There are three main ways that taurine works to improve bile metabolism. First of all, taurine stimulates the enzymes that synthesize bile from cholesterol. Second, taurine increases bile metabolism, resulting in the degradation of LDL by up-regulating the liver LDL receptor. Third, taurine binds to, or conjugates, bile acids, reducing the toxicity of bile acids (Murakami 2014). Bile acids can have a negative effect on mitochondria, causing dysfunction by being incorporated into mitochondrial membranes.

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Taurine-conjugated bile acids do not undermine mitochondrial function (Rolo et al. 2000; Sousa et al. 2015). Policosanols

Policosanols are a collection of long-chain alcohols, often extracted from the waxy coating on sugar cane. Policosanols can lower cholesterol in four ways: • inhibition of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis • accelerated degradation of HMG-CoA reductase • increased secretion of bile acids • increased clearance of LDL-C. (Haim & Videla 2008)

Policosanols are thought to positively act on cholesterol metabolism by raising the activity of the enzyme AMP-kinase (Zhou et al. 2001). AMP-kinase is an enzyme which also helps initiate mitochondrial biogenesis (Reznick & Shulman 2006). It comes as no surprise, then, that policosanols can help raise ATP and improve energy, as well as lower cholesterol (Long et al. 2015). It may be wise to supplement with CoQ10 when taking policosanols as HMG-CoA reductase is necessary for CoQ10 synthesis (Dixon et al. 2011). CoQ10 supplementation can help protect mitochondria from CoQ10 deficiency when taking an HMG-CoA reductase inhibitor (Hosseini & Mohammadi-Bardbori 2015). In several studies participants have been administered between 2 and 40mg of policosanols per day. All doses decreased LDL-C in participants, but doses over 20mg/d also increased HDL-C and doses of 40mg/d decreased triglycerides. As a rough guide for CoQ10 supplementation alongside policosanols, 50mg of CoQ10 twice a day has been found to reduce muscle-related symptoms in statin-prescribed patients (Skarlovnik et al. 2014).

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Red yeast rice

Red yeast rice is a popular nutraceutical which has been a folk remedy in Chinese medicine for centuries. It acts as both a nutrient and pharmaceutical: the active compound in red yeast rice is called monacolin K and is chemically the same as the statin drug lovastatin (Li et al. 2014). A variety of clinical studies have found that red yeast rice can lower serum LDL-C by between 10 and 33 per cent. However, red yeast rice doesn’t address the underlying health issues which lead to lipid imbalances, as any improvement in cholesterol is lost when the supplement is stopped (Li et al. 2014). In this sense, red yeast rice is more of a drug than a nutrient, even if it is more tolerable and has fewer side effects than pharmaceutical statins. CoQ10 should be supplemented when taking red yeast rice as it is a HMG-CoA reductase inhibitor. Mitochondria need to be protected against CoQ10 loss when HMG-CoA reductase is inhibited (Hosseini & Mohammadi-Bardbori 2015) by the statin-like actions of red yeast rice. As red yeast rice acts on the same pathway as statin drugs, it must not be taken in addition to medically prescribed statins. In a small-scale trial, patients taking either the nutraceutical or a statin had similar improvements in their lipid profiles (Ruscica et al. 2014). Olive oil

People consuming meals rich in extra virgin olive oil (for a month) have been observed to exhibit much lower levels of LDL-C and oxidized LDL-C compared to diets containing other oils (Violi et al. 2015).

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22 Autoimmune Disease The Emerging Field of Immunometabolism

Chapter 9, ‘Altering Immune Function’, examined the complex relationship between mitochondrial behaviour and the way immune cells express themselves – including autoimmunity. It used to be thought that something had to ‘make’ good cells turn ‘bad’ for autoimmunity to occur. Frustratingly, the cancer field still has this good/bad dichotomy as its dominant narrative. A newer narrative is that all cell conditions are within a complex gamut of behaviours/phenotypes of all cells. It’s less that a cell turns ‘bad’ and more that the environment is the ‘bad influence’ leading to damaging adaptive behaviours by a cell and tissue. Of course some autoimmune disease is genetic with familial origins, but diet and lifestyle choices are playing an increasingly important role in triggering autoimmunity. Modifying the immune system by altering cellular and mitochondrial metabolism is now recognized as an important biochemical category of its own – immunometabolism. A diet of foods low in micronutrient density and high in saturated fat and refined carbohydrates can lead to a kind of cell metabolism called aerobic glycolysis. Aerobic glycolysis is essential for growth and wound

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healing, but too much aerobic glycolysis can lead to excess growth and inflammatory immune system activity. Aerobic glycolysis is where a cell chooses to rely primarily on glycolysis for energy – even in the presence of oxygen. Aerobic glycolysis requires the glycolytic switch described previously in Chapter 7, ‘Synthesizing Cellular Components’. High-energy electrons are diverted away from energy production in the electron transport chain, to the synthesis of saturated fat and cholesterol for cell membrane synthesis. Inflammatory and autoimmune T cells rely on such rapid synthesis of cell wall lipids for their proliferation. Chapter 9 discusses how poor dietary choices can provide the right conditions for excess activation of autoimmune T cells through a shift to aerobic glycolysis. These include refined carbohydrates, excess saturated animal fat, trans/hydrogenated fat and low-fibre foods. There are a great many different antecedants, triggers and mediators of autoimmune diseases. This chapter focuses on some of the ways that mitochondria may be involved in the aetiologies.

Hashimoto’s thyroiditis Hashimoto’s thyroiditis is an autoimmune thyroid disease where the immune system produces antibodies against the thyroid gland. The two main markers for the disease are serum thyroglobulin (Tg) and thyroperoxidase (TPO) antibodies. The adipokine leptin is involved in Hashimoto’s thyroiditis, but, unusually, a major source of the leptin driving autoimmunity is thought to be T cells (S. Wang et al. 2013). Even though the main source of leptin is thought to be T cells, it is still wise to deal with excess adipose tissue-derived leptin. Insulin resistance and obesity can lead to increases in the circulating levels of leptin, which may undermine thyroid function and increase the chances of thyroid autoimmunity (Aeberli et al. 2010; Duntas & Biondi 2013). It’s not well known, but leptin has effects far beyond just the endocrine system. Immune regulation is an important property of leptin, and an excess of this adipokine can lead to a shift toward autoimmune T cell expression (Procaccini et al. 2015; Yadav et al. 2013).

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T regulatory cells have receptors for leptin. If circulating levels of leptin are high, then T regulatory cell expression can be suppressed, leading to increased expression of autoimmune Th17 T cells (S. Wang et al. 2013). It is likely that circulating adipose tissue-derived leptin may interfere with normal T cell leptin regulation. This implies that there is effectively ‘cross talk’ between adipose tissue and autoreactive T cells with increasing body mass index. In general, leptin supports mitochondrial function and biogenesis (Blanquer-Rossellõ et al. 2015), but, in excess, it can lead to an abnormal amount of lipid in the blood, inflammation and mitochondrial dysfunction (Vieira-Potter 2014).

Multiple sclerosis As we’ve seen, autoreactive Th17 T cells rely on aerobic glycolysis for them to proliferate and function. Mitochondria provide many of the raw materials for proliferating cells during aerobic glycolysis. The best proof that diet has a profound effect on autoimmunity is from the example of many multiple sclerosis patients. Multiple sclerosis patients who have adhered to an extremely healthy diet, such as the Swank diet (see Chapter 16, ‘Diets to Support Mitochondrial Function’), have displayed dramatically improved health – in some cases for up to 34 years (Taylor et al. 2014). Studies in animal models of multiple sclerosis have shown that blocking aerobic glycolysis can block a shift toward autoimmunity within  the immune system (Freitag et al. 2016). Autoimmunity is associated with a shift away from the production of protective T regulatory cells toward autoreactive Th17 T cells. In a similar way to Hashimoto’s thyroiditis, multiple sclerosis has links with increased circulating leptin. Leptin is an adipokine which assists T cells to shift their metabolism to aerobic glycolysis. Patients who were obese during their youth have been found to be more likely to suffer from multiple sclerosis in later life (Correale et al. 2014).

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Many multiple sclerosis patients have been very unfortunate in their early years to have suffered from abuse or trauma (Spitzer et al. 2012). Early-life trauma leads to thymic involution, or shrinking of the thymus gland, dramatically changing the way T cells are polarized (the way they are differentiated into Th subsets). Multiple sclerosis is also associated with premature thymic involution (Haegert & Haegert 2014), so it could be inferred from these findings that multiple sclerosis in patients displaying premature thymic involution could be linked to early-life trauma. Thymic involution does occur naturally with ageing, but with multiple sclerosis the involution occurs at a much younger age. In relation to the mitochondrial impact on thymic involution, some laboratory studies have shown that mitochondrial-targeted antioxidants can suppress age-related thymic involution (Shilovsky et al. 2015). DNA hypomethylation can lead to mitochondrial dysfunction (Singhal et al. 2015) and increased inflammatory gene expression (Yu & Kone 2004), and has been observed in multiple sclerosis patients (Sokratous et al. 2016).

DNA hypomethylation: a decrease in the epigenetic methylation of a gene, often leading to its over-expression.

It is imperative for multiple sclerosis patients to follow diet and lifestyle guidelines which help to support their thymus gland and produce healthier T cell populations. These guidelines are the following: • The patient should adopt a whole-food diet which protects against insulin resistance and aerobic glycolysis (please see the Swank and Wahls diets in Chapter 16, ‘Diets to Support Mitochondrial Function’). Remember, mitochondria turn from energy producer to inflammatory mediator during aerobic glycolysis. • The blood levels of vitamin D should be maintained at the higher end of the reference range as vitamin D suppresses the production of autoimmune T cells (Ascherio et al. 2010).

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• Patients should do everything within their power to look after their psychological well-being, avoiding unnecessary stress, including people and situations that cause stress, and seeking help if needed. Multiple sclerosis patients supported for stress tend to suffer from fewer brain and spinal cord lesions (Mohr et al. 2012).

Rheumatoid arthritis An extremely surprising finding from arthritis research is that naïve T cells of rheumatoid arthritis patients actually have excessively low levels of intracellular reactive oxygen species (ROS) leading to ‘reductive stress’, not oxidative stress, as would be expected. Rheumatoid arthritis patients have a defect in glycolysis which pushes too much glucose along the pentose phosphate pathway. This leads to the overproduction of nicotinamide adenine dinucleotide phosphate (reduced) (NADPH), which in turn leads to excessive reduced glutathione and too little ROS – a term known as reductive stress. This whole pattern causes naïve T cells to shift their polarization to autoreactive Th17 T cells and reduce their polarization to T regulatory cells (Yang et al. 2016). Increased reductive stress may also have the effect of raising cellular and mitochondrial nicotinamide adenine dinucleotide (reduced) (NADH), supplying more energy to mitochondria than they can handle – the result is that increased reductive stress can lead to the raised production of mitochondrial ROS (Pérez-Torres et al. 2017). In a cell-based study, mitoquinone was found to help reduce the likelihood of autoimmunity by quenching mitochondrial ROS (Freitag et al. 2016). It may seem contradictory that mitoquinone can lessen the likelihood of oxidative stress in mitochondria when excessive reductive stress is seen in rheumatoid arthritis. In truth, reductive stress and oxidative stress can occur simul-taneously within a cell. For example, in mitochondria, excessive NADH (reduced or reductive stress) can lead to oxidative stress, through the overdriving of the electron transport chain (Yan 2014). T effector cells (produced from Th cells and linked with autoimmunity) also have a high level of the glucose transporter GLUT1, whereas T regulatory cells (which protect against autoimmunity) have 198

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low levels of GLUT1 (Michalek et al. 2011). This implies that diets high in glucose and carbohydrate will be able to potentially polarize T cells to a Th17 phenotype. In an opposite manner to nutrient excess, anorexic and malnourished patients can suffer from immune deficiencies due to insufficient dietary stimulation of T cells (Gerriets & Rathmell 2012). Rheumatoid arthritis is more prevalent in women and, unfortunately (in common with multiple sclerosis), rheumatoid arthritis patients often suffer from early-life trauma. The negative autoimmune effects of the trauma may not be seen for many decades after the original insult (Spitzer et al. 2013).

Systemic lupus erythematosus In contrast to multiple sclerosis and rheumatoid arthritis, cell metabolism in lupus is quite different. In lupus, there appears to be insufficient aerobic glycolysis in T cells, leading to T cells suffering from mitochondrial dysfunction (Yang et al. 2015). Mitochondrial ROS do play a role in lupus, but there is a strange twist. Neutrophils actually export mitochondrial DNA to provoke an immune response. This is an important part of fighting infection, and is called a NET (neutrophil extracellular trap). It is likely that excess mitochondrial ROS in lupus will over-drive the formation of NETs, leading to destructive inflammation in lupus (Lood et al. 2016; West et al. 2011b). Like Hashimoto’s thyroiditis and multiple sclerosis, leptin has also been observed to be elevated in lupus. In animal models, blocking leptin activity was found to slow the progression of the disease (Lourenço et al. 2016). In lupus patients, 3g per day of fish oil (1800mg EPA (eicosapentaenoic acid), 1200mg DHA (docosahexaenoic acid)) for 120 days lowered leptin levels and resulted in a reduction of disease scores (Lozovoy et al. 2015). This all goes to show that modifying immunometabolism with diet, lifestyle and supplementation is not a ‘one size fits all’ approach. To have a positive effect on autoimmunity, the dietary interventions need

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to take into account the patient’s own individual needs, the disease, and the stage of the disease.

Key mitochondrial nutrients to consider in cases of autoimmune disease Vitamin D

Multiple sclerosis (Ascherio et al. 2010), rheumatoid arthritis (Colin et al. 2010) and lupus (Eloi et al. 2017) all have strong associations with vitamin D deficiency. Vitamin D plays an important role in blocking the Th17 polarization of T cells. As we’ve seen, Th17 polarization and the concomitant production of the cytokine interleukin 17 are a signature of T cell behaviour in autoimmunity (Colin et al. 2010). Vitamin A

In a similar way to vitamin D, vitamin A can help shift the polarization of T cells away from autoimmune Th17, toward T regulatory cells (Treg) (Elias et al. 2008). The ability of vitamin A and vitamin D to inhibit Th17 polarization of T cells can also support mitochondria, as mitochondrial dysfunction can be induced by Th17 T cells (Kim et al. 2017). Coenzyme Q10 (CoQ10)

Continuing on the theme of T cell polarization, CoQ10 is another compound that can enable a shift away from autoimmune Th17 T cells (Jhun et al. 2015). The quenching of mitochondrial ROS by CoQ10 can help protect against activation of Th17 T cells. Plant polyphenols: naringenin and EGCG

Plant polyphenols can act as pro-oxidants which activate the body’s own antioxidant defences in a process known as hormesis (please see Chapter 15, ‘Health, Toxicity and Hormesis’, for further information). Green tea exerts powerful effects on the immune system, mainly through the activity of the polyphenol EGCG (epigallocatechin-3gallate). In animal models, green tea is able to reduce inflammation, 200

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help shift T cell polarization away from autoreactive populations, and increase T regulatory cells (Wu et al. 2012). Multiple sclerosis patients supplemented for three months with EGCG have shown improvements in muscle energy metabolism (Mahler et al. 2015). Naringenin is a polyphenol found in oranges, grapefruit and tomatoes. In animal models of arthritis, naringenin can reduce joint inflammation and increase the expression of antioxidant enzymes (Fan et al. 2017). Naringenin is also protective against autoimmunity in animal models of multiple sclerosis (J. Wang et al. 2015). (Note that it is contraindicated with many medications.) α-Lipoic acid

α-Lipoic acid supplementation is proving to be beneficial in studies of multiple sclerosis patients. α-Lipoic acid can help reduce brain atrophy, improve blood–brain barrier integrity, reduce microglial activation and improve mitochondrial function (Spain et al. 2016). Participants in this study were supplemented with 1200mg of α-lipoic acid per day.

Microglia: specialized immune cells which reside in the central nervous system. Microglia are normally agents of healing and repair, but once active (or reactive) they can exacerbate brain injury.

In animal models of auto-immune arthritis, α-lipoic acid supplementation decreased joint destruction and many pathological aspects of the disease (Hah et al. 2011). Vitamin B12 injections

Vitamin B12 injections have been found to be helpful for patients with multiple sclerosis (Wade 2002). Could vitamin B12 injections be supporting the correct methylation of DNA? The evidence is limited, but one study found multiple sclerosis patients to have a 30 per cent increase in enzymes which remove methyl groups from DNA (Sokratous et al. 2016). As stated above, loss of methyl groups from DNA (or DNA hypomethylation) can lead to mitochondrial dysfunction (Singhal et al. 2015). 201

23 Fatigue

Patients with fatigue suffer from constant, debilitating low energy, and tire easily during exercise or take several days to recover. Many fatigue patients struggle to think clearly as they often complain of mental fatigue or a ‘brain fog’. Many medical practitioners have suggested fatigue to have biochemical and psychosomatic components, but there is increasing evidence for the involvement of mitochondria for many aspects of the condition.

PAMPs, DAMPs and inflammation as causes of fatigue Toll-like receptors are receptors of the innate immune system that sense the presence of microbial components. These microbial components are called PAMPs, or pathogen-associated molecular patterns. The immune system rapidly responds to PAMPs by inducing an inflammatory response and the release of reactive oxygen and nitrogen species (ROS and RNS).

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Large amounts of nitric oxide are induced by toll-like receptors (via DNA gene expression) to act as another microbial agent. Excess nitric oxide and other RNS are inhibitors of the mitochondrial electron transport chain. We can see from the above that when the innate immune system is dealing with bacterial infection, it could prove to be extremely difficult for mitochondrial energy production. Not only are mitochondria producing ROS to fight infection, but they are also themselves targets for RNS and ROS, produced by the immune system in the fight against infection. If the fallout from fighting an infection is excessive, then our own tissue, cells and mitochondria can become damaged by the immune system’s ROS and RNS ‘crossfire’. If compromised, these components of our own body become DAMPs, or damage-associated molecular patterns (Morris et al. 2015a). The innate immune system reacts to DAMPs as if they were a pathogen and can set up a vicious cycle of immune system hyperactivity. An initial inflammatory response may have been due to a pathogen triggering a toll‑like receptor, but chronic inflammation may be due to DAMPs. It is highly possible that a major factor in a patient moving from the experience of fatigue to chronic fatigue is the shift from PAMPs to DAMPs. DAMPs are likely to create even more DAMPs, unless the cycle of innate immune activation can be broken (Morris et al. 2015a). DAMPs can undermine mitochondrial function just as well as PAMPs. Unfortunately, dysfunctional mitochondrial components can be also DAMPs in their own right (Land 2015). This is not surprising, considering the bacterial origins of mitochondria. Failure to remove and replace worn-out mitochondria can also increase the chances of DAMPs triggering an innate immune system reaction. Mitophagy and mitochondrial quality control are therefore essential. Hence, one major cause of ongoing fatigue may be an initial inflammatory response to an invader (e.g. a bacterium) that has become chronic due to damaged mitochondria components perpetuating the inflammatory response.

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Low mitochondrial quality control Chapter 4, ‘Mitochondrial Dynamics’, examined the innate intelligence of mitochondrial self-management and how the organelles undergo constant quality control and renewal. Mitochondria have a shelf life which is numbered in days for most tissue. If mitochondria are not removed through mitophagy and replaced by biogenesis, then adenosine triphosphate (ATP) levels can plummet within a cell. Lack of exercise, excess calories and insulin resistance can all play a part in undermining mitochondrial quality control (Craig 2015; Jung & Kim 2014). Once a mitochondrion is working past its ‘use-by date’ then it is at real risk of increasing levels of ROS such as superoxide. It is frustrating for many people who have become out of condition through lack of exercise that they cannot simply start exercising when they realize their mistake. If their mitochondria are in poor shape, they may need a lot of biochemical support (such as resveratrol, EGCG (epigallocatechin-3-gallate), curcumin and omega-3 fatty acids, as discussed earlier) to help regenerate their mitochondria as they improve their exercise regime. Antioxidants may quench ROS from dysfunctional mitochondria, but mitophagy and mitochondrial biogenesis are needed to really bring mitochondria back to full working condition (Liang & Kobayashi 2016).

Insulin resistance and fatigue Underfunctioning mitochondria cannot metabolize lipids sufficiently, leading to an accumulation of lipids which will, in turn, exacerbate insulin resistance (Montgomery & Turner 2015). Therefore, insulin resistance can be both a cause and effect of mitochondrial dysfunction and fatigue.

DNA hypomethylation Methylation of DNA plays a crucial role in switching genes on and off, and it is the most common form of epigenetic modification. Although 204

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DNA hypomethylation is being discussed in this chapter, it is likely to be a factor in many other diseases. Patients with chronic fatigue have been found to have altered patterns of DNA methylation, with substantial hypomethylation of genes related to immune function. The overall effect of immune gene hypomethylation is to shift a person’s immune system toward a more inflammatory phenotype (De Vega et al. 2014). Mitochondrial genes will also be negatively affected by hypomethylation (Singhal et al. 2015). Inducible nitric oxide synthase (iNOS) is an inflammatory enzyme that is often found to be over-active in chronic fatigue. This over‑activity results in the production of high levels of nitric oxide which can bind to, and inhibit, mitochondrial complexes (Morris & Maes 2013). Hypomethylation of an iNOS gene promoter can be one reason for iNOS over-activity (Yu & Kone 2004). Large increases in cortisol have a negative impact on DNA methylation, particularly in a child’s formative years. In many people, as we saw for autoimmune diseases, it’s highly likely that later-life health issues can be traced back to early-life traumas or stresses (Nätt et al. 2015). Fatigue sufferers often benefit from vitamin B12 injections. Could it be that vitamin B12 injections are compensating not only for B12 deficiency, but are also helping to methylate and consequently repress inflammatory genes? Likewise, multiple sclerosis patients have found benefit from vitamin B12 injections (Wade 2002). Could high cortisol, experienced during early-life trauma, be playing a significant role in both these conditions? As stated in the previous chapter, loss of methyl groups from DNA (or DNA hypomethylation) can lead to mitochondrial dysfunction (Singhal et al. 2015).

Thyroid Mitochondria are under thyroid hormone control. This makes absolute sense, yet the profound effect of thyroid hormones on mitochondria is not widely known. It’s no wonder a hypothyroid patient feels such debilitating fatigue. 205

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The thyroid hormone T3 can: • stimulate oxidative phosphorylation • activate mitochondrial biogenesis • increase fatty acid β-oxidation. (Sinha et al. 2015)

Key mitochondrial nutrients to consider in cases of fatigue Taurine

Toll-like receptors of the innate immune system are now being considered as major players in fatigue and chronic fatigue syndrome (Gambuzza et al. 2015; Morris et al. 2015a). It therefore makes sense to find ways of reducing their negative effect on our own tissue, yet still allowing their antimicrobial activity to occur; taurine has the ability to do this. As discussed above, mitochondria play a pivotal role in toll-like receptor function. Taurine can moderate an excessive innate immune response and yet protect against an inflammatory injury during infection (Miao et al. 2011). An example of this taurine-related positive effect on the immune system occurs in neutrophils. Neutrophils are a type of lymphocyte which contain high levels of taurine, which is used to help protect the host tissue during an immune response (Kim et al. 2010). Taurine plays an important role in the building of the mitochondrial electron transport chain, being required to enable protein synthesis for the electron transport chain (Ito et al. 2012). Several studies have found that taurine can help in the recovery from fatigue after exercise. Interestingly, laboratory animals deficient in taurine have great difficulty in exercising and exhibit high levels of blood lactic acid (Takahashi & Hatta 2017). Ascorbate and α-tocopherol

In a similar way to taurine, ascorbate and α-tocopherol have been reported to reduce ‘collateral damage’ to our own tissue during an

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innate immune response. Individually, neither nutrient is as effective; this may be due to their synergistic quality, where they can recycle each other when oxidized (Chapple et al. 2013). Chronic fatigue patients have been found to have much lower blood levels of α-tocopherol compared to non-fatigued controls. This is thought to indicate the increased oxidative stress that occurs in fatigued patients (Miwa & Fujita 2009). Omega-3 fatty acids

Observations of chronic fatigue patients have found that they tested for low levels of omega-3 fatty acids relative to omega-6 fatty acids. In fact, it was found that a patient’s fatigue symptoms worsened as their omega-6 status increased (Morris & Maes 2014). Like taurine, ascorbate and α-tocopherol, omega-3 fatty acids exert a moderating effect on toll-like receptors (Lalia & Lanza 2016). Phospholipids

The phospholipid phosphatidylcholine has been shown to reduce inflammation associated with the activation of a toll-like receptor (TLR4). Conversely, the saturated fats palmitate and stearate were found to increase inflammation (Ishikado et al. 2009). Soy phosphatidylcholine was used in the study. Soy phospholipids contain omega-6 fatty acids, which may not be ideal for patients with fatigue. A marine source of phospholipids, such as krill oil, contains omega-3 fatty acids and could be more suitable for fatigue patients. Interestingly, a study found much reduced levels of oxidative stress in krill oil-supplemented athletes who were pushed to exhaustion (Skarpańska-Stejnborn et al. 2015). An additional benefit of krill oil is that it contains the carotenoid astaxanthin. Astaxanthin has been reported to be extremely effective in protecting mitochondria from oxidative stress (Wolf et al. 2010). ‘Lipid replacement’ with phospholipids has been cited as a way of helping to improve energy in chronic fatigue patients. The protocol is thought to work by replacing damaged cellular and mitochondrial lipid content (Nicolson & Ellithorpe 2006). From the above research examining the actions of phosphatidylcholine in toll-like receptors,

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it seems likely that immune system modulation may play a major role in the lipid replacement protocol. Citicoline is formed from choline and cytidine. It is a precursor to  phosphatidylcholine and can help prevent the loss of the mitochondrial phospholipid cardiolipin (Grieb 2014). Cardiolipin is a key component of the inner mitochondrial membrane and is attached to some of the electron transport chain complexes (Mejia et al. 2014). Although key for mitochondrial function inside a mitochondrion, outside a mitochondrion cardiolipin acts as a DAMP (Chakraborty et al. 2017) and triggers an inflammatory response. Increased blood levels of cardiolipin and antibodies to cardiolipin are indicative of cardiolipin which has escaped the confines of the mitochondrial electron transport chain. Fatigue patients often display increased blood levels of cardiolipin and antibodies to cardiolipin (Hokama et al. 2008). Vitamin D

Vitamin D can help reduce a heightened response of the innate immune system to PAMPs and DAMPs. Vitamin D does this via lowering the sensitivity of toll-like receptors to these inflammatory mediators. In this way, vitamin D can assist with immune system tolerance to excessive inflammatory stimuli (Ojaimi et al. 2013). Nowhere is the need for immune tolerance more acute than in the immune system balance between mother and baby. In a similar way to immune tolerance in an individual, vitamin D assists the delicate balance of immune tolerance between mother and baby (Tamblyn et al. 2015). Vitamin A

Vitamin A is yet another nutrient which works with toll-like receptors to help with immune tolerance (Manicassamy et al. 2009). Once again, if over-stimulated, the innate immune system will send signals to mitochondria to produce ROS instead of ATP. The thyroid hormone T3 is an important activator of mitochondrial function. Thyroid hormones need the assistance of vitamin A, as

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thyroid-responsive genes need to work side by side with the vitamin A-dependent retinoid X receptor (Sinha & Yen 2013). Vitamin A is an essential nutrient to help maintain the integrity of the intestinal wall, and to help prevent excess intestinal permeability (Baltes et al. 2004). Therefore, vitamin A can help prevent the translocation of gut bacteria into the bloodstream, thereby reducing the chances of innate immune system activation. As discussed above, innate immune system activation is thought to be over-activated in chronic fatigue patients. As important as vitamin A is, it is important to avoid excess vitamin A (e.g. a megadose of retinol is sometimes prescribed for acne treatment), due to its potential mitochondrial toxicity (de Oliveira 2015). Vitamin B12

Hypomethylation of inflammatory genes is often seen in chronic fatigue patients. Chronic fatigue patients often respond well to vitamin B12 injections. It could be that the benefit that many fatigue sufferers get from vitamin B12 injections is due to improved gene methylation. Professor Martin Pall is a world expert in the field of RNS (nitric oxide and peroxynitrite) and how RNS relates to chronic fatigue. Both nitric oxide and peroxynitrite can bind to, and inhibit, many complexes within mitochondria. Professor Pall suggests using vitamin B12 in the form of hydroxocobalamin as a nitric oxide scavenger (Pall 2001) to help improve energy levels in fatigue patients. B12 is generally considered to be safe, but it is concerning that some recent research has discovered high B12 levels in some cancer patients (Arendt et al. 2016). This is thought to be due to metabolic changes that occur during cancer, rather than B12 driving tumour growth. Nevertheless, it is wise to exercise caution, particularly if a patient is presenting with high B12 levels without supplementation. In cancer many protective genes are hypermethylated and switched off (Suvà 2013). So again, it’s important to be cautious with B12 and folate if a patient has, or is at risk of, cancer. As a safety precaution it would be wise to order a blood test to determine blood vitamin B12 and folate status before supplementing these nutrients.

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Coenzyme Q10 (CoQ10)

CoQ10 has shown promise in studies looking at supporting mental energy levels in fatigue patients (Fukuda et al. 2016). CoQ10 has also been found to reduce fatigue symptoms when combined with the supplement nicotinamide adenine dinucleotide (reduced) (NADH) (Castro-Marrero et al. 2015). Mitoquinone (a CoQ10 analogue) acts as a mitochondrial-directed antioxidant. The design of mitoquinone allows the compound to enter a mitochondrion far more easily than CoQ10 formulated as ubiquinone or ubiquinol (Kelso et al. 2001; Smith et al. 2004; Johnson & Grant 2015). Intestinal absorption of ubiquinone and ubiquinol is not very efficient and requires high doses of both these compounds to reach mitochondria (Garrido-Maraver et al. 2014). Mitoquinone has been reported to improve energy, mental clarity and sleep in fatigue patients. Impressively, fibromyalgia patients showed up to 33 per cent reductions in pain markers when they were supplemented with mitoquinone for six weeks (Johnson & Grant 2015).

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24 Neurodegeneration

Alzheimer’s disease and Parkinson’s disease are the two most common types of neurodegenerative disease. Mitochondrial dysfunction, inflammation, insulin resistance, misfolded proteins and oxidative stress can all have a major impact on both diseases. Misfolded proteins are a signature of neurodegenerative conditions and can greatly compromise mitochondrial function in their own right – but what exactly are misfolded proteins? Table 24.1 Misfolded proteins and disease: proteinopathies Proteinopathy

Misfolded protein

Alzheimer’s disease

Tau and amyloid β

Parkinson’s disease

α-synuclein

Creutzfeldt-Jakob disease (CJD – mad cow disease)

Prion protein

Type 2 diabetes

Amylin (islet amyloid polypeptide)

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Many proteins are folded to enable them to function correctly. When misfolded they clump together to form aggregates that stick to yet more proteins, interfering with their operation. In excess, misfolded proteins can trigger diseases known as proteinopathies (Golde et al. 2013). Alzheimer’s disease and Parkinson’s disease are two forms of proteinopathy.

The MAM: a mitochondrial membrane implicated in neurodegeneration The MAM (or mitochondria-associated endoplasmic reticulum membrane, to give its full name!) is a membrane which connects mitochondria with another important organelle – the endoplasmic reticulum. Two of the signature proteins involved in Alzheimer’s disease and Parkinson’s disease (amyloid β and α-synuclein) both have links with the MAM (Guardia-Laguarta et al. 2014; Schon & AreaGomez 2010). The MAM is of great interest to neurologists because of the many ways the MAM is associated with the pathological components of neurodegenerative disease. Researchers are developing a MAM hypothesis for both Alzheimer’s disease (Area-Gomez & Schon 2017) and Parkinson’s disease (Guardia-Laguarta et al. 2015). For such a seemingly insignificant membrane, the MAM has some highly significant effects on neuronal health. Calcium regulation, inflammation, cholesterol metabolism and mitochondrial dynamics are all themes which relate to the MAM. It is not hard to see why MAM dysfunction can play such a substantial role in neurodegeneration.

Calcium regulation The MAM connection between the endoplasmic reticulum (ER) and mitochondria allows the two organelles to co-ordinate regulation of cellular calcium. Poor calcium regulation is a problem common

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to Alzheimer’s disease and Parkinson’s disease, and the loss of MAM integrity can greatly undermine cellular calcium control. In fact α-synuclein, the protein misfolded in Parkinson’s disease, will undermine calcium homeostasis between the ER and mitochondria. Impaired α-synuclein within the MAM can subsequently lead to mitochondrial fragmentation (Calì et al. 2012). Please read Chapter 11, ‘Calcium Storage and Regulation’, for more information regarding the impact of calcium on mitochondria.

Inflammation Overly stressed mitochondria release components such as mitochondrial DNA and cardiolipin into the cytosol. Once outside mitochondria, these internal mitochondrial components trigger a strong inflammatory response via the activation of the inflammasome complex. In this way the loss of integrity in the ER–MAM mitochondrial unit can be a driver of damaging inflammation with a cell (Thoudam et al. 2016).

Cholesterol Apolipoprotein E is a cholesterol-carrying protein and is important for both cardiovascular and brain health (Liu et al. 2013). The ApoE4 isoform of apolipoprotein E has been found in many Alzheimer’s disease patients. The ApoE4 isoform increases the activity of the MAM, resulting in mitochondrial stress (Tambini 2016). This suggests that the cholesterol content of the MAM has a strong association with Alzheimer’s disease. The ApoE4 isoform of apolipoprotein E not only increases a person’s chances of atherosclerosis and Alzheimer’s disease but also, possibly, herpes virus and HIV infection (Pitas et al. 1987). Please read Chapter 21, ‘Cholesterol Metabolism’, for further information on mitochondrial associations with cholesterol.

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Mitochondrial dynamics: the MAM as a hub of activity for neuronal health Chapter 4, ‘Mitochondrial Dynamics’, described mitochondrial quality control and motility amongst many other themes. Fission and fusion and mitophagy are the processes at the core of mitochondrial quality control – all are connected with MAM activity. Mitochondrial motility requires mitochondria to be connected to a protein motor to drive the organelle along the cytoskeleton – again, the MAM plays an important part in this motor connection (Krols et al. 2016). Please read Chapter 4 for more information on mitochondrial quality control and motility.

Insulin resistance, type 2 diabetes and neurodegeneration Insulin resistance and type 2 diabetes increase the risk of Alzheimer’s disease and Parkinson’s disease (Aviles-Olmos et al. 2012; De Felice & Ferreira 2014). In fact, some researchers are now calling Alzheimer’s disease type 3 diabetes. In common with Alzheimer’s disease, insulin resistance in the brain can lead to cognitive decline and reduced function of the neurotransmitter acetylcholine (De La Monte 2008). Amylin is a little-known protein which is co-secreted alongside insulin. It plays a vital supporting role with insulin in controlling blood glucose. Continual high dietary glucose intake may lead to amylin misfolding (Abedini & Schmidt 2013). It has recently been suggested that misfolded amylin may interact with α-synuclein and could be yet another factor playing a role in Parkinson’s disease initiation (Atsmon‑Raz & Miller 2015).

Reductive stress In a similar way to metabolic syndrome, diabetes and rheumatoid arthritis, reductive stress is being found to play a role in neurodegeneration.

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To correctly fold proteins such as amyloid β, there have to be sufficient levels of oxidized glutathione in a cell to allow for the folding process. A lifetime of excess calories (through over consumption of macronutrients) leads to excessive amounts of the reduced energy carrier NADH (nicotinamide adenine dinucleotide (reduced)). Excess NADH creates a cellular ‘reduced’ environment which is not conducive to correct protein folding. Ironically the misfolded proteins triggered by reductive stress will lead to oxidative stress in mitochondria (Pérez‑Torres et al. 2017; Yan 2014).

Can Alzheimer’s disease and Parkinson’s disease be seeded? The action of misfolded proteins leading to further misfolding of intact proteins is known as seeding. We are now acutely aware of the dangers of misfolded proteins from the ingestion and seeding of prion proteins in Creutzfeldt-Jakob disease (CJD) (Green et al. 2008) when eating ‘infected’ meat. Seeding is the way that misfolded proteins cause a cascade of damage which allows aggregates or lumps of protein to transmit their damaging effects through the body. It has been suggested (Goedert 2015) that Alzheimer’s disease and Parkinson’s disease are caused in a similar way.

CREUTZFELDT-JAKOB DISEASE Creutzfeldt-Jakob disease (CJD – ‘mad cow disease’) is a transmissible neurodegenerative disease caused by aggregates of misfolded proteins known as prions. Although prions are aggregates of protein, they behave like an infectious agent due to their ability to damage and misfold adjacent proteins. This leads to a cascade of damaged proteins in the brain in a process known as ‘seeding’. Similar protein misfolding and seeding has been found to occur in both Alzheimer’s disease and Parkinson’s disease, but there is resistance to calling them prion diseases, due to the lack of evidence of transmission between individuals and other species.

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Could Parkinson’s disease start in the gut for some patients? In Parkinson’s disease, misfolded α-synuclein can often be found in the gut before any symptoms of Parkinson’s disease appear. One hypothesis is that aggregates of α-synuclein are ‘transmitted’ through vagus nerves from the gut to the brain in some Parkinson’s disease patients (Hawkes et al. 2007; Lema Tomé et al. 2012). Another theory, again related to the gut, suggests that imbalances in gut bacteria may be linked to neurodegeneration. Intestinal permeability is increased in Parkinson’s disease (Forsyth et al. 2011), allowing an easier transit of material from the gut to the brain. Lipopolysaccharide (LPS – a bacterial cell wall fragment) is thought to travel from the gut to the brain, to activate microglia, the resident macrophages of the brain (Forsyth et al. 2011; Mulak & Bonaz 2015). Once activated, microglia can release inflammatory cytokines which then damage and destroy neurons. Mitochondria within microglia are sensitive to the effects of LPS and release high levels of harmful reactive oxygen species (ROS) within activated microglia (Park et al. 2013). Furthermore, mitochondrial dysfunction in gut epithelial cells makes it very difficult for the cells to produce enough adenosine triphosphate (ATP) to maintain the integrity of cell junctions. If mitochondrial ATP levels fall, gut epithelial cells are likely to become more ‘leaky’ (Novak & Mollen 2015).

Tau proteins maintain neuron structure and energy supply Our cells contain a cytoskeleton which helps to maintain cell form and structure – cells are not just droplets of fluid encompassed by fat as often depicted in textbooks. In addition to structure, the cytoskeleton provides the tracks for a railway-like network to transport mitochondria, to be able to deliver their valuable energy load (Sato-Harada et al. 1996). Neurons are highly dependent on their cytoskeletons because of their long axons, which need a strong internal scaffold to support

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them (Sato-Harada et al. 1996). In the cellular world, neurons are tower block‑like structures – and just like a tower block, a neuron needs an internal cytoskeleton as a pillar of internal strength. Tau proteins are proteins that maintain the integrity of the cytoskeleton. In Alzheimer’s disease, tau proteins become dysfunctional, leading to the collapse of the neuronal cytoskeleton (Sendek et al. 2014). Without a robust cytoskeleton, mitochondria cannot reach the neuronal synapse where they are desperately needed for synaptic energy. Without tau protein to maintain the cytoskeleton, a neuron will collapse in on itself in a similar way to a demolished tower block.

Parkinson’s disease and mitochondria In Parkinson’s disease, it has long been recognized that a patient displays body-wide mitochondrial dysfunction, not just within dopamineproducing neurons (Clark et al. 2006). This is highlighted by the fact that the most commonly mutated genes in Parkinson’s disease are the genes that regulate mitochondrial quality control (Dagda & Chu 2009; Wang et al. 2011). Please refer to Chapter 4, ‘Mitochondrial Dynamics’, for further details on mitochondrial quality control. The uncoupling of Complex I of the electron transport chain (ETC) has been reported in Parkinson’s disease by many studies. Uncoupling leads to a dramatic increase in mitochondrial ROS, increasing the chances of cell death (Li et al. 2003). Rotenone, a pesticide used in organic farming, is an uncoupler of Complex I of the ETC and has been linked with Parkinson’s disease (Greenamyre et al. 2001; Naughton et al. 2017).

Key mitochondrial nutrients to consider in neurodegenerative disease Citicoline: CDP-choline (cytidine 5’diphosphocholine)

Citicoline acts as a precursor to many phospholipids (i.e. it helps provide the raw materials for these vital lipids) (Martí Massó & Urtasun 1991),

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essential for the structural integrity of neurons. As a separate action, citicoline is an inhibitor of PLA2, an enzyme which is up-regulated during neuroinflammation, which degrades phospholipids from cell membranes to liberate arachidonic acid. Excessive activity of PLA2 is seen in neurodegenerative disease, and citicoline can thus act as an inhibitor of this activity (Farooqui 2006). Citicoline is able to prevent the loss of the phospholipid cardiolipin from the inner mitochondrial membrane. This action of citicoline helps to maintain the function of the mitochondrial ETC and ATP synthesis (Gareri et al. 2015). Citicoline helps support the levels of the neurotransmitters dopamine, noradrenaline and acetylcholine (Cotroneo et al. 2013). Dopamine loss is seen in Parkinson’s disease, and acetylcholine loss is seen in Alzheimer’s disease. Therefore, citicoline is likely to support the activity of neurotransmitters in both conditions. Supplementation of citicoline, along with the omega-3 fatty acid DHA (docosahexaenoic acid) and uridine, is showing promise in animal studies looking at synapse formation. Synaptic loss, seen in Alzheimer’s and Parkinson’s disease, increases the need for these nutrients to help maintain synaptic function (Cansev et al. 2008; Wurtman 2014). Citicoline can help to maintain mitochondrial energy production – and has been found to be particularly supportive for synaptic mitochondria (Villa et al. 2012). As people age, it becomes increasingly difficult to incorporate choline into cell membranes. Citicoline has been found to improve the age-related deficit in membrane choline (Babb et  al. 1996). Citicoline can be synthesised in the body from dietary choline. Fish, eggs, meat and cruciferous vegetables are all good sources of choline. Omega-3 fatty acids

The omega-3 fatty acids DHA and EPA (eicosapentaenoic acid) are used to produce a set of compounds called ‘pro-resolving lipid mediators’. These pro-resolving lipid mediators are: resolvin, protectin, neuroprotectin and maresin. The compounds help to resolve inflammation and limit excessive immune activity which may damage us during infection and inflammation. Neuroprotectin is a DHA-dependent pro-resolving

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mediator and is particularly important in reducing neuroinflammation and protecting neural tissue. In the brains of Alzheimer’s patients, levels of neuroprotectin are often reduced (Serhan 2014). Coenzyme Q10 (CoQ10)

The mitochondrial ETC is essential for sufficient ATP synthesis in neurons. Additionally, maintaining its integrity is vital to protect against damaging mitochondrial ROS. The correct functioning of Complexes I, II and III of the ETC correlate well with adequate levels of CoQ10 in mitochondria. In Parkinson’s disease, the condition has strong associations with loss of Complex I activity and low CoQ10 within the substantia nigra. CoQ10 can also protect neurons in the substantia nigra from the toxic effects of α-synuclein and dopamine depletion (Spindler et al. 2009). In Alzheimer’s disease, CoQ10 has been shown to be beneficial in animal models for the condition. Researchers found that CoQ10 reduced plaque formation, defended against over-production of amyloid β, reduced ROS production and protected against memory loss (Spindler et al. 2009). Curcumin

Curcumin can help protect tau proteins from dysfunction and thus helps maintain the integrity of the cytoskeleton and guard against cytoskeletal degradation (Huang et al. 2014). As discussed above, in neurons the cytoskeleton forms the ‘railway tracks’ which help deliver mitochondria to the synapse – they are also an internal ‘scaffold’ giving form and structure to a neuron. When tau proteins malfunction, the cytoskeleton collapses, leading to a neuron retreating from a synapse with no track to deliver mitochondrial ATP (Matamoros & Baas 2016; Vickers et al. 2016). Curcumin works with both α-synuclein and amyloid β to help prevent toxic aggregation of these proteins (Ahmad & Lapidus 2012; Rao et al. 2015). Aggregates of α-synuclein and amyloid β have the ability to cause mitochondrial dysfunction and neuronal cell death (Angelova & Abramov 2016).

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Taurine

Blood taurine levels are decreased in Parkinson’s disease patients, with even further decreases found in patients undergoing L-DOPA therapy (L. Zhang et al. 2015). In fact, dopamine and taurine display a strong correlation in the striatum (a region in the basal ganglia of the forebrain) of animal models. This correlation has led researchers to believe that the two compounds may be linked in some way (Engelborghs et al. 2003).

L-DOPA THERAPY L-DOPA therapy is the gold standard medical therapy for Parkinson’s disease. Parkinson’s disease patients suffer from a loss of dopamine-producing neurons in the substantia nigra of the midbrain. The resulting drop in dopamine levels in the basal ganglia leads to the characteristic tremor seen in the disease. L-DOPA can help increase brain dopamine levels in Parkinson’s disease patients, thereby producing symptom relief and reducing their tremor. The dopamine precursor L-DOPA is given in preference to dopamine, due to the inability of dopamine to cross the blood–brain barrier.

Taurine has been found to be of benefit to dementia patients. Regarding Alzheimer’s disease, animal models supplemented with taurine in their drinking water showed a reduced number of cognitive issues and less amyloid β aggregates (H.Y. Kim et al. 2014). As mentioned in the section on curcumin above, misfolded amyloid β aggregates are toxic to mitochondria. In an in-vitro study, it was found that taurine could help protect against amyloid β-triggered mitochondrial dysfunction (Sun et al. 2014). Animal and human studies are needed to ascertain what sort of dose is worth trying. Vitamin A

Vitamin A, or retinoic acid, plays an important role in nerve regeneration, particularly the outgrowth of axons. Retinoic acid acts through DNA receptors to exert its regenerative effects. Loss of retinoic acid signalling is thought to lead to neuronal degeneration (Maden 2007).

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Axon outgrowth: the process of constructing an axon out of the cell body of a neuron. Axon outgrowth is required for the growth and repair of neurons.

Retinoic acid can help lessen microglial activation, thereby reducing inflammation. Microglia are the resident macrophages of the central nervous system – in other words they are part of the immune system of the brain. Microglial activation is seen in neurodegenerative disease, particularly when there is inflammation or there has been trauma (Hernandez-Ontiveros et al. 2013; Rojo et al. 2014). Traumatic brain injury can activate microglia and result in central nervous system inflammation. It is highly likely that Muhammad Ali had microglial activation as a major factor in the initiation of his own Parkinson’s disease symptoms as a result of his boxing career (Park 2016). Frustratingly, the degradation of retinoic acid is accelerated during microglial activation, highlighting the importance of increasing intake in neurodegenerative disease (Hellmann-Regen et al. 2013). Retinoic acid can enhance the activity of the neurotransmitter acetylcholine. The loss of acetylcholine function can result in the memory and cognitive issues seen in Alzheimer’s disease (Szutowicz et al. 2015). As promising as vitamin A is, in excess it can be toxic to mitochondria. Although all the mechanisms are not totally clear, vitamin A does appear to increase the toxicity of amyloid β and α-synuclein to mitochondria (de Oliveira 2015). As a precaution, check that serum retinol levels do not exceed the reference range.

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25 Cancer

Mitochondria are involved in cancer metabolism by at least two different paths. The first path is via providing the raw materials for rapid growth and proliferation. The second path is through mitochondrial control of apoptosis (programmed cell death), an important way to destroy tumour cells and thus help protect against cancer. It’s hard to understand why the powerful effects of diet, nutrition and lifestyle are seen as so ‘unscientific’ amongst cancer researchers, with such overwhelming evidence. Perhaps the ‘blind spot’ arises because of the difference between prevention and treatment of cancer? Dietary intervention can have a significant impact on the risk of cancer (Anand et al. 2008; Schwingshackl et al. 2017), and can also help improve survival if implemented by cancer patients (Schwedhelm et al. 2016). Frustratingly there is still a ‘blind spot’ regarding the protective effects of diet on cancer amongst medical professionals. This oversight continues to hinder the integration of dietary and medical intervention.

Risk factors for cancer initiation Risk factors for cancer initiation can be grouped into three major groups: 222

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• heritable: inherited gene mutations account for 5–10 per cent of all cancers • non-heritable intrinsic: gene mutations which accumulate over a lifetime • extrinsic: these are the risk factors associated with environmental inputs, including poor diet and lifestyle choices. (adapted from Birdsall 2016)

There is less that can be done to reduce the first two risk factors, but an enormous amount can be done to limit the effect of extrinsic risk, through diet and lifestyle modification. Individuals are not totally to blame for their extrinsic risk, as society does impose a considerable amount of toxicity on an overly trusting populace. Pesticides, environmental pollutants, plastic additives and asbestos all play their part in increasing extrinsic risk for all of society.

Is cancer a metabolic disease? Non-heritable and extrinsic cancers are still considered to be caused only by mutations. This is the somatic mutation theory (SMT), which holds that it’s the accumulation of DNA mutations that initiates uncontrolled cell proliferation. However, the SMT fails to explain many types of cancer, particularly hormonal cancers, where the removal of a hormonal stimulus can lead to cancer regression and apoptosis (Sonnenschein & Soto 2016). It is difficult to support cancer patients nutritionally when thinking only within the mutation paradigm. More and more research is now pointing to cancer being a metabolic disease (Hainaut & Plymoth 2012), which supports the use of nutrition. More importantly, a major failing of the mutation theory of cancer is that it fails to acknowledge the central role mitochondria play in cancer. Other theories have always existed about cancer causation; it is just that,  until recently, the SMT theory has dominated academic and medical thinking. It is well known that obesity and type 2 diabetes have strong associations with cancer (Gallagher & LeRoith 2015). But, does this mean that obesity and type 2 diabetes trigger high levels of DNA mutation? 223

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Or is it more realistic to see both conditions as being inflammatory, proliferative states which drive cellular growth excessively? Is a mutation the only way to initiate cancer? Or could there be a tipping point where excess inflammation leads to a cell losing the ability to restrain its growth? It is so important to ask these questions, as more evidence about the complexities of cancer metabolism emerges. One of the beliefs that has kept the mutation theory as the dominant theory of cancer causation for 100 years is that a cell requires a DNA mutation to trigger uncontrolled growth. However, rapid growth is likely to be innate within all our cells (Soto & Sonnenschein 2004), so that our tissue can rapidly heal when wounded. There is an evolutionary ‘wildness’ to all our cells, harnessed and tamed in healthy tissue – left unbridled, our cells may run amok. Therefore, a mutation may not be needed at all to initiate cancer – in fact many cancers are now accepted as being purely inflammatory in origin (Coussens & Werb 2002). A change in the cancer causation paradigm from mutation to metabolic (by which we mean inflammation and proliferation) allows for a more integrated approach to the disease. The efficacy of more subtle support, such as nutrition, can be better appreciated when examining cancer metabolism beyond mutation. The subtleties of how a cell calls on mitochondria to enable growth can then be acknowledged.

Can nutrition support cancer patients? Healthy diet and nutrition may help to protect against cancer initiation and support patients with cancer (Pal et al. 2012). However, cancer metabolic pathways need to be understood to be able to take full advantage of the anti-proliferative attributes of nutrition. Two useful resources to help the reader understand cancer metabolic pathways are: ‘Mitochondrial dysfunction and redox imbalance as a diagnostic marker of “free radical diseases”’ (Georgieva et al. 2017) and ‘Polyphenolic nutrients in cancer chemoprevention and metastasis: role of the epithelial-to-mesenchymal (EMT) pathway’ (Amawi et al. 2017). That’s not to say that nutrition is the ‘be all and end all’ in cancer support – far from it. In the face of cancer, nutrition is more powerful

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than generally acknowledged, but far less powerful than we would like. For good reason, the 1939 Cancer Act makes it illegal for non-medical practitioners, or non-medical interventions, to claim that they can treat cancer. The downside of the Cancer Act is that it may lead to the medical profession overlooking vital scientific evidence in relation to the integration of mainstream medicine with nutrition. For example, curcumin, an extract from the spice turmeric, has been found in numerous studies to work synergistically with chemotherapy, with dramatic increases in the efficacy of both agents (Sreekanth et al. 2011).

Employing subtlety and co-operation to support cancer patients Immersing ourselves in the metabolic paradigm of cancer allows us to examine the exquisite metabolic mechanisms that link health, chronic disease and cancer – but as a continuum, not as a sudden random event. Mutations can play a major role in cancer, but perhaps a lesser role than presently accepted. Mutation theories also encourage an adversarial type of intervention – somehow the tumour is no longer ‘us’, and this may encourage an aggressive war against cancer. Yes, aggressive interventions may be needed, but in the end, the final solution in life is always diplomatic. Interventions that take into account every facet of tissue, cell and mito-chondrial behaviour could, in a way, be likened to metabolic diplomacy. What actually enables the success of complex human multi-celled life is the co-operation, not competition, between tissues in the body. Cancer can be seen as a loss of tissue co-operation in exchange for an increase in tissue competition. Frustratingly, cancer cells co-operate all too well with each other, but to the detriment of other tissue. Remember from Chapter 2, ‘Enabling Evolution’, that it was the cooperation between mitochondria and cells that allowed for the amazing creativity of all our cells. Loss of cell co-operation, as seen in cancer, is in effect a ‘devolution’ of cells and tissue (Setälä 1984).

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Nutritional support aims to help restore cell and tissue co-operation from the wildness of competition, by using natural compounds that work with our metabolism. Where diet and nutrition may be particularly helpful is in their ability to help block the initiation of many cancers (Pal et al. 2012).

Mitochondria and uncontrolled growth Aerobic glycolysis (see Chapter 7, ‘Synthesizing Cellular Components’) is the preferred metabolism for rapidly proliferating cells (Gatenby & Gillies 2004) as it allows the mitochondria to switch to an anabolic ‘cellbuilding mode’. In anabolic mode, mitochondria help to provide many of the raw materials for proliferation (Icard et al. 2012). In Chapter 7, the shift in metabolism was described as being similar to mitochondria morphing between a power station and a builder’s merchant. In catabolic ‘power station’ mode, the carbon ‘bricks’ from food are released as CO2. In anabolic ‘builder’s merchant’ mode, the carbon bricks are exported by mitochondria to help make the carbon skeletons for fatty acid, protein and nucleotide synthesis. In cancer, the sequestering of citrate and oxaloacetate (precursor to aspartate) from the TCA (tricarboxylic acid) cycle helps to provide some of the raw materials for biosynthesis. This loss of the TCA cycle intermediates is compensated for by supplying glutamate or glutamine to the TCA cycle. The entry of glutamate or glutamine derived α-ketoglutarate into the TCA cycle (through anaplerosis, the entry of compounds into the TCA) is an important source of carbon to help maintain mitochondria as suppliers of components for biosynthesis and proliferation (DeBerardinis et al. 2008). The supply of glutamine or glutamate to tumour cell mitochondria is known as glutaminolysis (Jin et al. 2016). The dietary excesses behind obesity and type 2 diabetes may lead to a surplus of TCA cycle intermediates. In these conditions it may be essential to export citrate and aspartate to maintain the function of the TCA cycle. Excess cytosolic citrate and aspartate may trigger excess proliferation – in fact, drugs that block excess aspartate synthesis have been found to block tumour growth (Sullivan et al. 2015). 226

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Apoptosis Mitochondria may help drive growth and proliferation, but through apoptosis (programmed cell death) they can also help protect against cancer. Natural killer cells and cytotoxic T cells can both detect tumour cells and act as a death stimulus to initiate apoptosis (Martínez-Lostao et al. 2015). Inside a cell, the death stimulus leads to mitochondrial cytochrome c being released from the electron transport chain, forming an apoptosome, and the production of cell death proteins (Adrain & Martin 2001).

Key mitochondrial nutrients to consider in cancer prevention and care Please note: non-medical practitioners prescribing these should be working in conjunction and co-operatively with the medical team. Curcumin

As we have seen, curcumin has many healing and protective properties, which are being revealed by scientific studies. At the time of writing, there are over 108,000 studies listed in the Google Scholar database under the search terms ‘curcumin’ and ‘cancer’. One of the most important properties of curcumin is its ability to inhibit or suppress the activity of the pro-inflammatory transcription factor NF-kappa B. Transcription factors such as NF-kappa B act as intermediaries between a receptor on a cell surface and DNA. In this way, NF-kappa B is an inflammatory go-between from a signal on a cell surface to inflammatory gene switches within DNA. If this ‘go-betweenness’ of NF-kappa B could somehow be suppressed, then inflammatory signals could be blocked. Curcumin does exactly this – it partially blocks or suppresses NF-kappa B, and literally ‘shoots the inflammatory messenger’. Every time you read about the pro-cancer effects of NF-kappa B below, think: ‘Curcumin can help to suppress this!’ So why is a suppressor of inflammation like curcumin also protective against cancer? This is where the metabolic theory of cancer 227

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fits in – the theory that there is a continuum between inflammation, proliferation and tumour initiation. NF-kappa B has a powerful effect on cancer‑related gene expression, leading to increases in the following cancer-related mechanisms: • Inflammation: in the metabolic theory of cancer, inflammation is the first step toward tumour growth. • Survival: normally cells should undergo apoptosis after a period of time – in cancer, cells become immortalized and NF-kappa B helps a cell to evade its programmed death. • Proliferation: a replicating cell goes through a cycle of growth, DNA synthesis and division. NF-kappa B helps speed up this process. • Invasion: NF-kappa B triggers the expression of proteins which enable tumour cells to break free from their tissue constraints and adhere to other tissue. • Angiogenesis: the growth of blood vessels toward a tumour increases blood and nutrient supply – and allows a route for tumour cells to invade other tissue. NF-kappa B increases the expression of a blood vessel growth promoter called vascular endothelial growth factor (VEGF). • Metastasis: further invasion of tumour cells to tissue and organs is called metastasis. NF-kappa B helps express a protein called a chemokine, which accelerates metastasis. (Aggarwal 2009)

NF-kappa B plays a role at every step of the cancer continuum – and unsurprisingly mitochondria are influenced by this inflammatory transcription factor. The export of citrate/acetyl-CoA from mitochondria switches a cell to ‘anabolic mode’ and helps to favour inflammation and proliferation in tissue. The citrate carrier (CIC) enables mitochondria to export citrate. CIC is a protein whose expression is increased by NF‑kappa B (Infantino et al. 2014). Citrate/acetyl-CoA exported from mitochondria is used to synthesize saturated fatty acids such as palmitate (via the enzyme fatty acid synthase). In breast cancer, palmitate binds to many receptors and proteins – a process called palmitoylation. Excess palmitoylation 228

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can be a factor driving breast tumour growth (Anderson et al. 2016). Over‑expression of fatty acid synthase is seen in breast, prostate, ovarian and many other cancers. In vitro, curcumin has been found to protect against breast cancer by inhibiting fatty acid synthase (Fan et al. 2016). Tamoxifen is a chemotherapy drug which is a type of selective oestrogen receptor modifier (SERM). Many patients develop resistance to chemotherapy drugs, including tamoxifen. The induction of NF‑kappa B by chemotherapy drugs is a major problem as it can enable pro-survival mechanisms which block chemotherapy actions (Jiang et al. 2013; Li & Sethi 2010). Curcumin can help overcome chemoresistance by inhibiting NF-kappa B and increasing the efficacy of many chemotherapy drugs (Jiang et al. 2013; Shakibaei et al. 2013). The ultimate aim of many chemotherapy drugs is to initiate apoptosis, a process initiated by mitochondria. NF-kappa B can increase the expression of proteins that block apoptosis (Aggarwal 2009); therefore curcumin supplementation can help allow chemotherapy drugs to overcome mitochondrial resistance to apoptosis.

P53: THE TUMOUR SUPPRESSOR PROTEIN In addition to curcumin’s ability to be an effective inhibitor of NF‑kappa B, curcumin can also increase the expression of the tumour suppressor protein p53 (Das & Vinayak 2015; Li et al. 2015). p53 is mutated in many cancers (Khoo et al. 2014) and epigenetically suppressed or silenced in others (Herrero et al. 2016; Llinàs-Arias & Esteller 2017). A key action of p53 is to trigger mitochondria to initiate apoptosis in tumour cells, but mutated p53 loses its ability to target mitochondria for apoptosis (Mihara et al. 2003). p53 mutation is therefore a major issue in cancer pathogenesis and highlights the fact that the metabolic theory of cancer doesn’t have all the answers. p53 and NF-kappa B are mutual arch-enemies; where NF‑kappa B protects tumour cells, p53 destroys them (Pal et al. 2014). p53 is therefore a vital protein to help protect against, and destroy, tumour cells.

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Plant polyphenols

From the above, it may sound like curcumin is all that we need to protect ourselves against inflammation and cancer. As brilliant as curcumin is, there are many, many more natural compounds that have inhibitory effects on inflammation and proliferation. Variety is not only the spice of life, it also helps to protect against cancer. On the theme of variety, a study looking at lung cancer risk amongst smokers found that it was the variety of fruit and vegetables that they consumed, not the amount, that protected smokers from cancer (Hou & Kumamoto 2010). As we’ve seen earlier, calling plant polyphenols ‘antioxidants’ really misses what these wonderful natural compounds are doing. To be a little pedantic, they are actually quite strong pro-oxidants which initiate a strong endogenous antioxidant reaction, via the antioxidant response element (ARE) within DNA. This is known as ‘hormesis’ (see Chapter 15, ‘Health, Toxicity and Hormesis’), where a small amount of toxicity elicits a powerful protective response from the body (Biasutto et al. 2011; Thangapazham et al. 2006). Another problem with calling plant polyphenols ‘antioxidants’ is that some oncologists may wrongly assume that many of these plant compounds will interfere with chemotherapy. Frequently, this is not the case, but the research databases should always be thoroughly examined with a patient’s oncologist to ensure that a polyphenol supplement will be appropriate. In addition to hormesis, plant polyphenols act to suppress cellular signals (via proteins) which would normally trigger inflammation and proliferation. This is in a similar way to curcumin inhibiting NF-kappa B activity. The signal proteins that plant polyphenols modify include Akt, MAPK, JAK, PI3K and Raf (Hou & Kumamoto 2010). Many of these signal proteins translocate to mitochondria, implying that mitochondria are likely to be important communication hubs for proliferative signals (Lim et al. 2016). In another protective mechanism, plant polyphenols interact with many cell signals and proteins, to help mitochondria initiate apoptosis in tumour cells.

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Table 25.1 Foods and their associated polyphenols that support mitochondria in triggering apoptosis Food source

Polyphenol

Green tea

EGCG (epigallocatechin-3-gallate)

Grapes, red wine, peanuts, mulberries

Resveratrol

Soybeans, peas, lentils

Genistein

Turmeric

Curcumin

Pomegranate

Anthocyanins and ellagitannins

Strawberry, grapes, onion, cucumber, apple

Fisetin Source: Khan et al. (2008, 2010)

β-Glucans

There are a wide variety of food and supplementary sources of β-glucans, a group of polysaccharides found in the cell walls of mushrooms, yeast, oats, barley and rice. Fungal β-glucans are known as PAMPs (pathogen-associated molecular patterns), which our innate immune system sees as evidence of a fungal infection. It’s the activation of the immune system by β-glucans that gives some mushrooms their cancer-protective effect. For this reason, β-glucans are known as biological response modifiers (Brown & Gordon 2005; Volman et al. 2008). As discussed in Part I, plant chemicals can be detrimental at higher doses, and this threshold varies from person to person. It’s important to  prescribe a personalized dose (taking into account a person’s ability to mount a hormetic response, their genetics to express endogenous antioxidants, their present toxic load, and how many other compounds they are consuming) to avoid the risk of an immune system imbalance. When we eat mushrooms, our body is not sure if we are eating food or are suffering from a fungal infection. By selecting mushrooms with

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beneficial biological effects, we get the benefits of a food source along with an innate immune system boost. Although it’s now taken for granted, over millennia our ancestors have carefully selected and cultivated food sources which not only taste good, but elicit a beneficial biological response. It’s frustrating that a lot of humanity has lost its way with the healing properties of food, and instead choose harmful, health-negating food products. One group of immune cells increased by exposure to β-glucans are natural killer cells. Natural killer cells are one of the most important populations of lymphocyte in the body’s fight against cancer (Richter  2016). Natural killer cells activate apoptosis mechanisms in tumour cell mitochondria, which then lead to tumour cell death (Fan et al. 2011; Schwartz & Hadar 2014; Zhang et al. 2014).

MUSHROOMS WITH POTENTIAL ANTI-TUMOUR EFFECTS •

Shiitake (Mantovani et al. 2008)

•

Agaricus blazei (Mantovani et al. 2008)

•

Maitake (Alonso et al. 2017)

•

Reishi (Suarez-Arroyo et al. 2013)

•

Chaga (Ning et al. 2014)

•

Cordyceps sinensis (Jayakumar et al. 2014)

Omega-3 fatty acids

Omega-3 fatty acids can help protect against cancer in several different ways. Membrane signal disruption

In a similar way to plant polyphenols, the omega-3 fatty acids DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) can help disrupt inflammatory and proliferative cell signals. However, rather than interfering with signalling proteins, DHA and EPA disrupt cell membrane structures to alter the way proliferative signals pass through. Again, a major effect of this disruption is to increase the expression of proteins that trigger apoptosis with the assistance of mitochondria (D’Eliseo & Velotti 2016; Gu et al. 2013). 232

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Antagonism of cyclooxygenase and lipoxygenase

Omega-6 fatty acids are the precursors to the inflammatory enzymes cyclooxygenase (COX) and lipoxygenase (LOX) – both families of enzymes are implicated in tumour growth. Omega-3 fatty acids are natural antagonists of omega-6 fatty acids and, consequently, of COX and LOX (Beloribi-Djefaflia et al. 2016; Gu et al. 2013). Toll-like receptors

Toll-like receptors, or TLRs, are the receptors that recognize fragments of bacterial cell wall. When a bacterial infection occurs, TLRs react by helping to trigger an inflammatory immune response. Sadly, excess activation of TLRs is linked to inflammation and cancer, particularly colon cancer. In this way, pathogenic bacteria in the colon could be linked with colon cancer (Abreu 2010; Schwabe & Jobin 2013). TLRs can become over-reactive when in the presence of excess saturated fat, but are far less reactive in the presence of DHA (Gu et al. 2013). TLRs trigger mitochondria to produce reactive oxygen species (ROS). The increase in mitochondrial ROS in Helicobacter pylori infection is thought to be one of the main triggers for gastric cancer (Yuan et al. 2013). ROS production to fight microbes is part of a mitochondrion’s many roles, but, in excess, can lead to inflammation and possibly cancer (Tait et al. 2012). Let’s re-examine the above slowly to dig down and look at the implications: • Helicobacter pylori infection can lead to fragments of Helicobacter pylori cell wall activating receptors of the innate immune system called toll-like receptors. (‘Toll’ means excellent, cool, awesome or weird in German – German researchers cried ‘Toll’ as they found this bacteria-sensing receptor.) • A TLR can be hyper-responsive to bacteria in the presence of excess saturated fat. This is more likely to be a problem for people with insulin resistance, metabolic syndrome and type 2 diabetes who have mitochondria in ‘anabolic mode’. Remember, ‘anabolic mode’ is when mitochondria are exporting citrate for fat and cholesterol synthesis, rather than using citrate for adenosine 233

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triphosphate (ATP) synthesis (see Chapter 7, ‘Synthesizing Cellular Components’). Fifty per cent of the world’s population have a Helicobacter pylori infection, so the metabolic environment of the host must play a major role in gastric cancer initiation (given that a far lower percentage of those infected go on to develop cancer). The omega-3 fatty acid DHA can make a TLR less hyper-responsive (Lee et al. 2003). Both EPA and DHA can also reduce the export of citrate from mitochondria (Ferramosca & Zara 2014). • TLR activation triggers mitochondria to produce ROS. This is normal for mitochondria as it’s their job to pull together with the immune system to help destroy pathogens. • Mitochondrial ROS activate inflammatory responses and DNA damage (Tamura et al. 2013). • Along with other insults, continued exposure to mitochondrial ROS in the stomach can initiate gastric cancer, as they can trigger chronic inflammation and DNA instability/mutations in gastric epithelial cells. Which one is the primary event to initiate cancer – chronic inflammation or DNA instability? Or are both of equal influence? PPARγ

The omega-3 fatty acids EPA and DHA can bind to a nuclear receptor called PPARγ. PPARγ is a tumour suppressor which also assists mitochondria in starting the apoptosis process, to kill tumour cells (Gu et al. 2013). Resolvins

EPA and DHA are the precursors to the anti-inflammatory, inflammation-resolving compounds called resolvins (Gu et al. 2013). It is thought that the anti-inflammatory, tumour-suppressive effects of omega-3 fatty acids may in part be due to resolvins (Moro et al. 2016). In addition to tumour cells depending on glycolysis through the Warburg effect (see Chapter 7, ‘Synthesizing Cellular Components’), we now know that mitochondria are far from passive in this process.

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Tumour cells require fats and cholesterol to build membranes and to help provide the cell signals that stimulate proliferation; by exporting citrate/acetyl-CoA, mitochondria are providing the building blocks for endogenous lipid synthesis. This is what is referred to as ‘anabolic mode’ in this book. Modifying or blocking endogenous lipid synthesis is therefore likely to be protective against cancer, and studies have confirmed this with omega-3 fatty acids (Jump 2008; Mashima et al. 2009). Tumour cells have been found to be enriched with fat. Excessive lipid content in a tumour cell can lead to a tumour behaving more aggressively and becoming increasingly resistant to chemotherapy. Dietary saturated fat intake could also be potentially used by tumours to escalate cell proliferation (Beloribi-Djefaflia et al. 2016). CLA: conjugated linoleic acid

At a cellular level, ketogenic diets can support mitochondria, encourage apoptosis and inhibit aerobic glycolysis – all protective against cancer. Caution should be exercised when choosing fat sources for a ketogenic diet to protect against cancer. This is because the long-chain saturated fat palmitate has been shown to be incorporated into aggressive tumours, accelerating tumour growth (Louie et al. 2013). In relation to colon and liver cancer, any increase in all types of dietary fat may raise the risk of these cancers. A high fat diet increases the production of secondary bile acids which have tumour-promoting potential (Ocvirk & O’Keefe 2017; Xie et al. 2016). CLA is another fatty acid receiving a lot of attention in cancer research. CLA is an inhibitor of fatty acid synthase, the enzyme that converts citrate/acetyl-CoA from mitochondria into the harmful endogenous saturated fats such as palmitate (Donnelly et al. 2009). Evidence from research suggests that CLA is a much stronger inhibitor of tumour growth than omega-3 fatty acids. CLA supplementation has shown some  promising outcomes in many tumour cell lines, such as in prostate and breast cancer (Koba & Yanagita 2014). The richest dietary CLA sources are beef and dairy products but these sources may be contraindicated in cancer due to their high content of inflammatory long-chain saturated fatty acids such as palmitate.

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Long-chain saturated fatty acids are also contraindicated in ketogenic diets for cancer, due to the proliferative nature of these fatty acids. For example, the excess binding of palmitate to cell regulatory proteins (palmitoylation) has been found to play a role in breast cancer metastasis (Anderson & Ragan 2016). Like omega-3 fatty acids, CLA can bind nuclear fatty acid receptors and influence mitochondria-driven apoptosis (Koba & Yanagita 2014).

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26 Osteoarthritis

Osteoarthritis is often called a ‘wear and tear’ disease, or is seen as the type of arthritis that doesn’t involve the immune system. These old beliefs about the disease can now be seen as simplistic at best. It’s now accepted that the immune system is definitely involved in osteoarthritis, and that wear and tear is less of an issue – it’s the reparative process that is dysfunctional. In a similar way to fatigue and many other conditions, damaged tissue and cellular components can act to drive excessive and destructive inflammation. In the right amounts, these DAMPs (damage-associated molecular patterns) should initiate a healing inflammatory response. In excess, DAMPs can lead to a downward spiral of cartilage and joint degeneration because the inflammation process continues long-term. Lifelong over-consumption of simple carbohydrates and poor blood‑sugar regulation can lead to the formation of advanced glycation end-products, or AGEs. AGEs are proteins or lipids incorrectly modified by sugar. AGEs are subsequently detected by the immune system as a type of DAMP – AGEs have their own receptor called a RAGE (receptor for advanced glycation end-products). Cartilage has RAGEs, and once

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RAGEs are activated they can produce destructive inflammatory cytokines (Goldring & Otero 2011). Obesity is not only a physical load on cartilage and joints, it’s also an immune and metabolic load. The infrapatellar fat pad within the knee can release cartilage-destroying adipokines in obese individuals (Goldring & Otero 2011).

Mitochondria and osteoarthritis With recent rapid developments in science, we now have a greater understanding of the metabolism of chondrocytes, the cells which aggregate together to help form cartilage and the extracellular matrix (a network of proteins and polysaccharides produced outside cells in many types of tissue). Chondrocytes are heavily dependent on mitochondria for their energy, and it is the dysfunction of chondrocyte mitochondria that can leave chondrocytes vulnerable to damage and unable to produce the energy and raw materials necessary for their continual repair and replacement. Mitochondrial dysfunction has been associated with many of the issues that lead to the breakdown and apoptosis of chondrocytes. These include inflammation, impaired growth and repair, and increased oxidative and nitrosative stress (damage to proteins from excessive nitric oxide) (Blanco et al. 2011). When compared to healthy chondrocytes, chondrocytes from osteoarthritis patients show lower activity of Complexes I, II and III of the mitochondrial electron transport chain (Blanco et al. 2011). Ironically, many of the non-steroidal anti-inflammatory drugs (NSAIDs) used to relieve the symptoms of osteoarthritis increase the degradation of cartilage (Hauser 2010). NSAIDs are inhibitors of Complex I of the mitochondrial electron transport chain and can cause a dramatic increase in toxic mitochondrial reactive oxygen species (ROS) production (Sandoval-Acuña et al. 2012). The loss of mitochondrial adenosine triphosphate (ATP) and rise in mitochondrial ROS due to NSAIDs is highly detrimental to chondrocytes struggling to maintain cartilage integrity.

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Key mitochondrial nutrients to consider in osteoarthritis Coenzyme Q10 (CoQ10)

In animal models, CoQ10 is able to reduce pain and inflammation in osteoarthritis. Inflammatory cytokines, inducible nitric oxide synthase (iNOS) and RAGE expression were all reduced by CoQ10 supplementation (Lee et al. 2013). Hyaluronic acid, glucosamine and chondroitin sulphate

Collectively, hyaluronic acid, glucosamine and chondroitin sulphate are known as ‘chondroprotectives’. All three are components of synovial fluid and cartilage within joints. Hyaluronic acid is a polysaccharide important for the physical synthesis of cartilage and also for the protection of chondrocyte mitochondria. Hyaluronic acid is able to reduce inflammation, nitric oxide and ROS synthesis and to protect mitochondria from initiating apoptosis in chondrocytes (Grishko et al. 2009). The unique properties of hyaluronic acid enable it to act as an anti-inflammatory lubricant which coats and protects the cartilage of joints. Hyaluronic acid is able to retain water in cartilage (and is used to good effect in solutions to relieve dry eye syndrome) (Singh et al. 2014). In a similar way to hyaluronic acid, glucosamine and chondroitin sulphate can support the physical repair of cartilage and simultaneously act as anti-inflammatory agents (Jerosch 2011). Many cynical commentators question the ability of glucosamine and chondroitin sulphate to be of benefit in osteoarthritis, due to the difficulty of these compounds to reach damaged cartilage. The finding that chondroprotectives are anti-inflammatory and hyaluronic acid in particular is protective of mitochondria (Grishko et al. 2009) will, it is hoped, silence these critics! Omega-3 fatty acids

The omega-3 fatty acids DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid), used in combination with glucosamine sulphate, exhibit powerful anti-inflammatory effects in patients with osteoarthritis. In addition, omega-3 fatty acids can help increase

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collagen synthesis and suppress the activity of cartilage-degrading enzymes (Jerosch 2011). Vitamins C and E

Osteoarthritis patients are often found to test for low levels of antioxidants. Vitamin C is required for collagen synthesis and is protective of knee cartilage. Vitamin E has been found to improve chondrocyte growth and reduce joint pain. Vitamin E has been shown to have similar pain-reducing effects to some NSAIDs at a dose of 600mg per day for ten days (Jerosch 2011; Wang et al. 2004). Please be aware that vitamin E supplementation may negatively interact with the drugs aspirin, warfarin, tamoxifen and cyclosporine A (Podszun & Frank 2014). Curcumin

Curcumin has extremely poor bioavailability, and many supplement manufacturers continue to develop formulations to help improve absorption of this anti-inflammatory spice extract. One such formulation is where curcumin is bound to a molecule of phosphatidylcholine. The addition of phosphatidylcholine to curcumin potentially increases its absorption 20-fold. This form of curcumin has been shown dramatically to decrease osteoarthritis symptoms by 50 per cent when supplemented for a year (Belcaro et al. 2010).

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27 Osteoporosis

Bone requires high levels of energy to maintain its integrity and is consequently extremely dependent on mitochondria. In ageing bone there is a shift away from energy production in mitochondria to the production of energy through glycolysis. Upon examination, osteocytes (a type of cell found in bone) have been found to have swollen mitochondria, indicating a high probability that these organelles are dysfunctional (Shum et al. 2016). Osteoporosis research is shifting more toward a focus on mitochondrial function and away from the previous oestrogen focus. That is not to say that oestrogen isn’t important, just that oestrogen probably exerts its benefits via actions on bone mitochondria. For example, oestrogen up-regulates mitochondrial superoxide dismutase, an enzyme that is important for mitochondrial function (Z. Liu et al. 2014). In animal models of osteoporosis, loss of mitochondrial superoxide dismutase (SOD2) leads to an increase in bone loss and a decrease in bone formation. Ageing bone was found to have dramatically higher levels of mitochondrial superoxide compared to younger bone osteocytes (Kobayashi et al. 2015).

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Although far less common, osteoporosis also occurs in men and can be related to a deficiency in testosterone, steroid use or alcohol. Thirty per cent of all hip fractures are seen in elderly men, but unfortunately many are not treated or diagnosed due to osteoporosis being largely seen as a post-menopausal female disease (Vanderschueren 2015). Tamoxifen is a drug which blocks oestrogen receptor activity to help treat women with hormone-sensitive cancers. Tamoxifen use leads to increases in mitochondrial superoxide, lower levels of SOD2 and, consequently, reduced bone growth. The herbicide paraquat is a toxic compound known to raise mitochondrial superoxide. Paraquat exposure can also lead to bone loss and abnormalities (Kobayashi et al. 2015).

Key mitochondrial nutrients to consider in osteoporosis Shiitake and maitake mushrooms

The balance between osteoblasts (cells that build bone) and osteoclasts (cells that break down bone) is vitally important in maintaining bone integrity. If the balance shifts excessively toward osteoclast activity, then the seeds for osteoporosis can be planted. Osteoclasts are the resident macrophages of the bone – instead of engorging pathogens, they effectively digest bone, as part of a continual process of building up and breaking down bone. The dietary mushrooms shiitake and maitake both exhibit inhibitory effects on osteoclasts in animal models. Shiitake mushrooms have the additional benefit of being able to increase the activity of bone-building osteoblasts. Researchers found that shiitake and maitake mushrooms were able to decrease bone loss in the lumbar spine in animal models of osteoporosis (Erjavec et al. 2016). Although research doesn’t yet make a definite link between shiitake and maitake mushrooms and protection of mitochondria, a possible link is that yeast and mushroom polysaccharides act as superoxide scavengers and support the antioxidant NADPH quinone reductase (Fortin et al. 2017). NADPH quinone reductase has the ability to activate CoQ10 (Ross & Siegel 2018).

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Resveratrol

Like shiitake and maitake mushrooms, resveratrol suppresses the activity of osteoclasts and enhances the activity of osteoblasts (Mobasheri & Shakibaei 2013). Oxidative stress within bone (e.g. mitochondrial superoxide) can increase the activity of osteoclasts, leading to excessive bone resorption. Oxidative stress can also lead to the loss of bone-building osteoblasts, due to damaged mitochondria triggering apoptosis in these cells (He et al. 2015). In a cell-based study, resveratrol, acting through the anti-ageing protein SIRT1, suppressed oxidative stress and inflammation in bone. In this study, resveratrol helped protect against mitochondrial-driven apoptosis in osteoblasts (He et al. 2015). Garlic

Allicin, a compound found in garlic, can help prevent osteoblasts from undergoing apoptosis. Allicin was shown to block mitochondria-driven apoptosis when osteoblasts were exposed to reactive oxygen species (ROS) (Ding et al. 2016). Curcumin

Curcumin can help initiate mitochondrial apoptosis in osteoclasts. In animal models, curcumin can decrease bone resorption by osteoclasts by up to 80 per cent. Curcumin inhibits the activity of RANKL (receptor activator of NF-kappa B ligand), a protein that can drive the growth of osteoclasts (Rohanizadeh et al. 2016). Lupeol

Lupeol is a compound found in cabbage, peppers, strawberries, olives, mangoes, grapes and dandelion coffee. Like curcumin, lupeol is an inhibitor of RANKL and so reduces the activity of osteoclasts (Im et al. 2016; Saleem 2009). RANKL is up-regulated in ageing bone by decreased expression of mitochondrial superoxide dismutase (Kobayashi et al. 2015). Lupeol and curcumin could therefore help to protect bone from an age-related reduction in mitochondrial antioxidant activity.

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Calcium

Calcium supplementation is the most often suggested supplement for osteoporosis prevention and intervention – but is it a wise choice? There is no doubt that calcium is essential for bone, but does supplemental calcium also increase the risk of other diseases? Although controversial, some research has shown calcium supplementation to be associated with an increased risk of cardiovascular disease and artery calcification. One study found a 22 per cent increased risk of arterial calcification in people supplementing calcium for ten years (~90–1200mg/d). Interestingly, the risk of calcification was greater in people supplementing calcium and who had a low dietary intake of calcium (Anderson et al. 2016; Tankeu et al. 2017). This highlights the importance of dietary calcium over supplementary calcium. In another study, which followed women aged between 57 and 90 years of age, total calcium intake of up to 1200mg per day (combined dietary and supplementary intake) resulted in high blood and urinary calcium in 8.8 per cent and 30.6 per cent of women respectively. The study found that even a level of 600mg of calcium citrate per day may be too much for some women. The authors recommend testing blood and urinary calcium before supplementing, and then at three-month intervals during supplementation (Gallagher, Smith & Yalamanchili 2014). What is a major concern with supplemental calcium is how an ageing nervous system deals with a concentrated amount of calcium entering into the body. In neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, poor mitochondrial calcium handling leads to neuronal death (Abeti & Abramov 2015). Such calcium mishandling can be due to excitotoxicity, misfolded proteins, low magnesium, inflammation, oxidative stress, excessive saturated fat, excessive aerobic glycolysis, high simple carbohydrates and reductive stress – see Chapter 11, ‘Calcium Storage and Regulation’. Before supplementing calcium in the elderly, there does need to be an appropriate risk assessment of the impact that calcium supplementation may have on the whole of a patient’s metabolism. If supplementing calcium, another point to consider is that several co-factors are needed to assist calcium in bone building. Magnesium, vitamin D3, vitamin K2 and boron can all support calcium when 244

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protecting against osteoporosis. Two forms of calcium supplement suggested to have a good safety profile are ossein-hydroxyapatite and AlgaeCal. Ossein-hydroxyapatite has been shown to be more effective than other forms of calcium at maintaining and increasing bone mineral density (Castelo-Branco & Dávila Guardia 2015). In a seven-year study, AlgaeCal was impressively able to increase bone mineral density by 7.3 per cent, which equates to a year on year increase in bone mineral density of 1.03 per cent (Kaats et al. 2016). The addition of vitamin K2 to a calcium supplement can help protect against arterial calcification. Vitamin K2 is a co-factor for the GLA matrix protein, a protein which inhibits calcium from binding to blood vessels and soft tissue (El Asmar et al. 2014). Taurine

The release of hypochlorous acid by neutrophils acts as an antimicrobial agent during infection. When combined with taurine, hypochlorous acid becomes taurine chloramine. Taurine chloramine can undermine the metabolism and synthesis of osteoclasts at several levels (Sam & Lu 2009) and thus help to prevent bone resorption. Neutrophils have an unusual use for mitochondria. Neutrophils seem to not use mitochondria for energy but they do export them to elicit an immune response called NETs (neutrophil extracellular traps) (Yousefi et  al. 2009). Hypochlorous acid is a driver of NET formation (Palmer et al. 2012) and consequently mitochondrial export from neutrophils. The neutrophil link to osteoporosis is also highlighted by a closer examination of white blood cell ratios. The neutrophil to lymphocyte ratio (NLR) is being found to correlate better with osteoporosis in postmenopausal women than C-reactive protein (Yilmaz et al. 2014). An average NLR of 4.68 was found in osteoporosis patients compared to an NLR of 2.01 in controls. This ratio is easily obtained from routine haematology tests (Yilmaz et al. 2014). Additionally, taurine can help support bone via another mechanism. To assist in protecting bone, taurine can act as an agent to promote the differentiation of stem cells into bone-building osteoblasts (Zhou et al. 2014).

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28 Chronic Pain

Although pain medication has become extremely advanced, the actual causes of pain have been little understood by conventional medicine, resulting in much suffering for many patients. In a similar way to fatigue, the subtlety of the condition has led to it being marginalized and sufferers seen as ‘weak’ or ‘slackers’. If we don’t understand something we often call it psychosomatic, suggesting that the condition is all in the person’s head – in other words, imagined. Even if a condition is psychosomatic, it is nevertheless very real for the person suffering. Like many conditions, major inroads are being made into our understanding of pain, and these ‘roads’ pass through the nervous, immune and energy-producing systems. Chronic pain can come from two sources – inflammation-related pain, or pain from aberrant signals within the nervous system (neuropathic pain). Inflammatory pain emanates from damage to tissue; neuropathic pain is due to damage to the nervous system. Chronic pain is defined as persistent pain that continues even after an injury has healed (Sui et al. 2013). Mitochondria are involved in many aspects of both inflammatory pain and neuropathic pain; mitochondrial adenosine triphosphate (ATP),

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reactive oxygen species (ROS), calcium and cell death pathways have all been implicated (Sui et al. 2013). It may seem counterintuitive, but recent research has found that blocking complexes of the mitochondrial electron transport chain (ETC) can help relieve pain (Sui et al. 2013). This does seem a worrying strategy, especially after the concerns raised in Chapter 24, ‘Neurodegeneration’. In that chapter, Parkinson’s disease and its relation to defects in the ETC was discussed. However, the pain-relieving effects of ETC suppression do show that, once again, mitochondrial ATP is involved in more than just energy. In Chapter 9, ‘Altering Immune Function’, the way mitochondrial ATP is used as an extracellular immune system signal was discussed. The nervous system uses extracellular ATP in a similar way to the immune system, interacting with a network of purine receptors (adenosine is a purine). Higher extracellular ATP levels correlate with increased activation of purine receptors and heightened pain. Purine receptors are the subject of much research into pain and how pain is perceived. We can now see that unless ATP export or purine receptors are quietened within the nervous system, then increasing mitochondrial ATP for pain sufferers may be counterproductive. Another reason that increases in ETC activity may increase pain is that dysfunctional mitochondria may concomitantly increase reactive oxygen and nitrogen species. Reactive nitrogen species such as nitric oxide and peroxynitrite can perturb cellular calcium metabolism, also leading to increased neuropathic pain (Grace et al. 2016).

Key mitochondrial nutrients to consider in cases of pain Magnesium

Mitochondria are very sensitive to calcium influx via the N-methylD-aspartate receptor. Mitochondrial dysfunction caused by high mitochondrial calcium is one of the main drivers of excitotoxicity. Magnesium has the ability to suppress the activity of the N-methyl-Daspartate receptor, a glutamate receptor linked to pain hypersensitivity, to help alleviate pain. Magnesium sulphate given intravenously after

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surgery has been showing very good analgesic effects in many studies (Crosby et al. 2000; Venturini et al. 2015). In women suffering from fibromyalgia, magnesium in the form of magnesium citrate at a dose of 300mg per day was able to reduce the number of tender points they experienced. In the study, magnesium deficiency was common in fibromyalgia patients, with symptoms correlating with the level of magnesium deficiency (Bagis et al. 2013). Please read the section ‘Excitotoxicity’ in Chapter 11, ‘Calcium Storage and Regulation’, for more on excitotoxicity and the N-methylD-aspartate receptor. The process of excitotoxicity is believed to be implicated in neuropathic pain. Vitamin C

The analgesic properties of vitamin C are thought to be due to its ability to suppress the activity of the N-methyl-D-aspartate receptor. This effect occurs in a similar way to magnesium and so protects mitochondria from calcium excess (Saffarpour & Nasirinezhad 2017). When supplemented in cancer patients, there is the additional benefit that opiate medication can be reduced, to lessen the toxic effects of the drug. Because vitamin C is cleared so rapidly via the kidneys, vitamin C does need to be administered throughout the day (Carr & McCall 2017). Chilli: capsaicin

Neuropathic pain is transmitted through vanilloid receptors within the peripheral nervous system. Capsaicin, an extract from chilli, is an agonist of vanilloid receptors which depolarizes and deactivates them, leading to pain relief. Capsaicin can be delivered as a cream or skin patch (Gálvez et al. 2016). A likely mechanism for capsaicin’s analgesic effect is through the death of sensory neurons due to capsaicin overdriving mitochondria within these cells (Shin et al. 2003). Therefore, the initial burning and heat sensation from chilli peppers is probably the feeling of our sensory neuronal mitochondria in overdrive! Pushing sensory neurons into excitotoxicity and apoptosis is rather extreme, so capsaicin should only be administered with the help of an appropriately qualified practitioner.

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Understanding how capsaicin functions in the nervous system highlights the primary role that mitochondria have in transmitting pain signals in sensory neurons. It is really interesting to see that by destroying mitochondria in sensory neurons, capsaicin is able to block the transmission of pain – after the initial ‘burn’ sensation. Ginger

Gingerols are a group of pungent compounds contained in ginger. Like capsaicin they act on vanilloid receptors on sensory nerves, altering calcium signals through nerve mitochondria (Dedov et al. 2002). Gingerols are weaker agonists of vanilloid receptors and therefore do not exhibit the toxicity of capsaicin. Ginger has been shown to be an analgesic for women with dysmenorrhoea. Ginger supplemented during the first three to four days of the menstrual cycle was found to be useful for reducing the symptoms of dysmenorrhoea (Daily et al. 2015). B vitamins

The B vitamins B1, B6 and B12 have all been assessed for their analgesic effects in many studies. Although the studies are often on a small scale, time and again this combination of B vitamins shows substantial pain‑relieving effects for many patients (Gazoni et al. 2016). Vitamin B6 as pyridoxal 5’-phosphate (PLP) is thought to reduce pain by blocking activation of the mitochondria-dependent inflammasome complex (Zhang et al. 2016). Professor Martin Pall has a great interest in the use of vitamin B12 as a scavenger of nitric oxide for patients with fibromyalgia and chronic fatigue (Pall 2010). Nitric oxide is a precursor to the radical peroxynitrite (mitochondria are a significant source), a molecule known to increase pain signalling (Janes et al. 2012; Radi et al. 2002). It is highly likely that the analgesic effect of vitamin B12 is due to its ability to reduce levels of peroxynitrite within the nervous system. The link between the analgesic effect of vitamin B1 and mitochondria is not clear. However, the pivotal role that vitamin B1 plays in the pyruvate dehydrogenase complex suggests there could be a strong association.

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Vitamin D

US military veterans suffering from chronic pain were found to have low serum vitamin D levels. Supplementation and normalization of serum vitamin D resulted in reductions in pain and the numbers of areas of pain, pain medication, and improvements in sleep and general quality of life (W. Huang et al. 2013). Vitamin D is an important regulator of calcium and mitochondria. If vitamin D is low, then mitochondria in muscle cannot utilize calcium effectively, resulting in fatigue (Sinha et al. 2013). It’s interesting that calcium and mitochondria are involved in pain signalling – could it be that vitamin D is working to control calcium and mitochondria in sensory neurons?

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29 Depression

The causes of depression will be unique to an individual, with psychological and biochemical factors interacting in a highly complex manner. This chapter does not seek to undermine the psychological aspect of depression in any way. However, there are many biochemical or dietary associations with depression that are often under-acknowledged. This chapter seeks to examine the mitochondria-related biochemical aspects of depression. The central nervous system (CNS) is highly dependent on mitochondria to provide the energy needed to maintain the function of the complex network of neurons that constitute the brain. It therefore comes as no surprise that researchers have now discovered that people with depression have impaired CNS energy production (Bansal & Kuhad 2016). Additionally, the fallout from energy production can have a negative impact on the neurotransmitters most related to depression. These are the monoamines serotonin, dopamine, adrenaline and noradrenaline. Mitochondria-derived reactive oxygen and nitrogen species (ROS and

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RNS)9 can undermine the enzymes that synthesize monoamines (Bansal & Kuhad 2016) – this is one of the mechanisms that leads to dopamine loss in Parkinson’s disease, when tyrosine hydroxylase (the enzyme that helps in the synthesis of dopamine, adrenaline and noradrenaline) becomes dysfunctional. Monoamine oxidase A and B are enzymes involved in the degradation of monoamine neurotransmitters – these two enzymes are anchored to the outer mitochondrial membrane (Bansal & Kuhad 2016). Firstgeneration anti-depressant drugs were monoamine oxidase inhibitors and prolonged the life of these ‘feel-good’ neurotransmitters. As we age, the activity of monoamine oxidase enzymes increases, accelerating the degradation of monoamine neurotransmitters. This acceleration of monoamine oxidase could be due to increased oxidative stress, since the antioxidant carnosine has been found to slow down the activity of the enzyme (Banerjee & Poddar 2015). A degradation product of dopamine is DOPAL, a metabolite which is toxic to mitochondria. Once inside a mitochondrion, DOPAL has to be degraded by mitochondrial aldehyde dehydrogenase (Marchitti et al. 2007), an enzyme whose activity decreases with age and oxidative stress (McCarty 2013). A reactive degradation product of serotonin is the less-studied 5-HIAL (Alleman et al. 2014). 5-HIAL is very similar to DOPAL from dopamine and is therefore very likely to be just as toxic to mitochondria. So if chronic psychological stress induced by oxidative and nitrosative stress are added to the mix, this will lead to a further rise in monoamine degradation, more toxic monoamine metabolites and increased mitochondrial dysfunction. Another downside of monoamine oxidase activity is that, for every monoamine degraded, a molecule of hydrogen peroxide is produced. Hydrogen peroxide (or any ROS in excess) can lead to the damage of many cellular components including lipids, proteins and DNA. Excess ROS production is implicated in depression and psychiatric disorders (Salim 2014). The antioxidant enzymes glutathione peroxidase and 9 Chronic psychological stress can drive the production of mitochondrial ROS and RNS through its ability to undermine oxidative phosphorylation in mitochondria (Bansal & Kuhad 2016).

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catalase are required to metabolize hydrogen peroxide to water (Bansal & Kuhad 2016). From the above, it is clear that chronic psychological stress-induced mitochondrial dysfunction can trigger a chain of events which can damage or destroy part of the nervous system. At the best of times, monoamine metabolism produces a substantial amount of reactive intermediates. Under psychological stress, this metabolism may be pushed to the brink – and beyond.

Synaptic plasticity Mitochondria are transported in large numbers along neuronal cytoskeletal tracks to provide the energy to help build and maintain the integrity of synapses. The outgrowth of synapses toward dendrites is essential to allow adaptation to a variety of psychological stresses – this is known as synaptic plasticity (Bansal & Kuhad 2016). When mitochondria are dysfunctional, synaptic plasticity decreases, leading to increased difficulty controlling and recovering from negative mood (Marsden 2013).

Neurogenesis and nerve growth factor Slowed neurogenesis (including mitochondrial biogenesis) will mean that a person may not be able to adapt to changing environmental and psychological circumstances (Bansal & Kuhad 2016). In order to enable neurogenesis to take place, mitochondria have to accumulate at the site of axon growth. Nerve growth factor (NGF) is a protein which is required to allow for this mitochondrial accumulation (Hroudová & Fišar 2011). Depressive patients have been found to test for low serum levels of NGF (Wiener et al. 2015). Conversely, romantic love is able to raise levels of NGF (Emanuele 2011) and so increase axon growth. These findings raise important issues about the importance of human connection in depression and throughout life. It is fascinating

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how mitochondria can respond to love and human connection (via NGF) and so repair neurons damaged by chronic stress.

Neuronal signalling and calcium Calcium within a neuron acts as an important signalling molecule. Mitochondria modulate neuronal calcium signals and so play an important role in cellular calcium balance. When dysregulated, calcium can trigger mitochondria to destroy neurons in a process called excitotoxicity (Pivovarova et al. 2004). Excitotoxicity has been found in hippocampal neurons of depressive patients (Campbell & MacQueen 2004) (see the section ‘Excitotoxicity’ in Chapter 11, ‘Calcium Storage and Regulation’). From the above two sections we can see that mitochondrial dysfunction can lead not only to decreased hippocampal neurogenesis, but also to increased hippocampal neuronal death, through excitotoxicity.

Genetics Gene analysis has found an increase in polymorphisms that disrupt the expression of the protein SIRT1 in people with depression. SIRT1 is an essential protein for the process of mitochondrial biogenesis (Cai et al. 2015).

Antibiotics Antibiotics could provide a surprising link with depression. From Chapter 2, ‘Enabling Evolution’, we discovered that, millions of years ago, mitochondria were once a type of α-proteobacteria. The bacterial ancestry of mitochondria means that they are incredibly vulnerable to antibiotics, with the aminoglycosides being some of the more troublesome subtypes of antibiotic (Stefano et al. 2017). Optimum brain function and sense of well-being will be undermined if excessive 254

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neuronal mitochondria are lost. Research supports this hypothesis, with the risk for depression or anxiety increasing for each successive course of antibiotics (Lurie et al. 2015).

Inflammation Lower intake of omega-3 oils and higher intake of simple carbohydrates can lead to inflammatory shifts within the immune system, which also have a disastrous impact on the brain (Bergmans & Malecki 2017; Gangwisch et al. 2015; Grosso et al. 2014). Mitochondria form part of the inflammasome complex (see Chapter 9, ‘Altering Immune Function’), the activation of which has strong links with depression (Alcocer-Gómez et al. 2014; Zhou et al. 2011). As a point of interest, SSRI (selective serotonin reuptake inhibitor) medication has strong anti-inflammatory effects within the CNS, in addition to stabilizing serotonin levels (Tynan et al. 2012).

Exercise Many studies have found that aerobic exercise can be of tremendous benefit to patients suffering with depression. The research suggests that three supervised 30-minute sessions a week to around 70 per cent of maximum heart rate can be effective (Perraton et al. 2010). This is unsurprising considering how hungry the brain and mitochondria are for oxygen. From the above section on genetics, it can be seen that expression of SIRT enzymes can be highly protective against depression. Exercise increases the expression of SIRT enzymes, and SIRT enzymes in turn are needed to help maintain the production of new mitochondria through mitochondrial biogenesis (Kincaid & Bossy-Wetzel 2013; Menzies et al. 2013). Chronic stress can suppress the expression of SIRT1, leading to atrophy of hippocampal regions of the brain (Abe-Higuchi et al. 2016). The hippocampus region of the brain is the area most associated with depression. 255

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Leptin and metabolic syndrome Leptin is a hormone released by adipose tissue that has a suppressive effect on appetite and increases mitochondrial metabolism (Singh et al. 2009). Obesity and leptin dysregulation are associated with depression (Milaneschi et al. 2015). Consumption of excess calories in obese people could in part be self-medication to try to raise functional low leptin levels. (This situation can arise in obesity due to leptin resistance.) Insulin resistance and metabolic syndrome commonly occur in depressive disorders and may exacerbate depression or depressive symptoms. Depressive patients with metabolic syndrome may also be more resistant to anti-depressant medication (C.S. Liu et al. 2014). Mitochondria are strongly linked to the pathology of insulin resistance and metabolic syndrome. For more information, please read Chapter 18, ‘Insulin Resistance and Type 2 Diabetes’.

Key mitochondrial nutrients to consider in depression Magnesium and zinc

Magnesium and zinc are important regulators of glutamate receptors within the central nervous system. Both these ions can regulate glutamate-dependent excitatory neurotransmission, and help prevent excitotoxicity. Excitotoxicity occurs when excess or unregulated glutamate allows calcium to flood into a neuron, overwhelming mitochondria and leading to neuronal death (see Chapter 11, ‘Calcium Storage and Regulation’). Magnesium and zinc have both been found to have strong antidepressant effects, thought to be due to their ability to decrease glutamate-dependent neurotransmission (Mlyniec 2015). Patients with major depressive disorder have been found to have low serum magnesium and high serum calcium (Deb et al. 2016). Low concentrations of magnesium at the glutamate receptor may lead to a greater risk of excitotoxicity. High serum calcium concentrations may lead to a greater influx of calcium into an excitatory neuron, leaving its mitochondria more vulnerable to stress and dysfunction. 256

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Folate

The monoamine neurotransmitters serotonin, dopamine and noradrenaline are dependent on hydroxylase enzymes for their synthesis. Serotonin requires the enzyme tryptophan hydroxylase, and the catecholamines (dopamine and noradrenaline) require tyrosine hydroxylase. An essential cofactor (an organic compound or metal ion necessary for the function of an enzyme) required for these two hydroxylase enzymes is tetrahydrobiopterin, or BH4. BH4 is vulnerable to oxidative stress and once oxidized cannot convert the amino acids tryptophan and tyrosine to their respective serotonin and dopamine precursors. Folate metabolism is closely associated with BH4, with folate as its active methylated form having the ability to activate and stabilize BH4 (Stahl 2008). Folate deficiency has long been associated with depressive disorders, and what is even more positive about supplementing folate is its synergism with SSRI anti-depressant medication. In patients who are non-responsive or partially responsive to SSRIs, methylfolate supplementation proved to be an effective and safe addition to the medication (Papakostas et al. 2012). In animal models, mitochondrial DNA (mtDNA) is more susceptible to mtDNA deletions or mutations when folate is in short supply (Crott et al. 2005). Interestingly, there is some evidence that an increase in mtDNA deletions occurs during depressive disorders (Kato et al. 2011). Risk factors for folate deficiency are: • • • • •

high alcohol intake gene polymorphisms in folate metabolism gastrointestinal disorders pregnancy drugs with anti-folate side effect (e.g. methotrexate, antimalarial medication) • high-measured homocysteine (and obviously low-measured folate). (Stahl 2008)

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Vitamin C

Vitamin C displays a similar positive synergistic effect with antidepressant medication (Aburawi et al. 2014). And in common with folate, vitamin C can help stabilize and increase cellular levels of BH4 (Yacoub & Altamimi 2016). Mitochondria are a major source of cellular ROS and it is therefore unsurprising that they have a large requirement for antioxidants such as vitamin C. Mitochondria even have their own vitamin C transporters to meet their need for this vital antioxidant (Szarka & Balogh 2015). Caffeine

In a cell-based study, caffeine has been shown to induce PGC-1α, the co‑activator for mitochondrial biogenesis (Vaughan et al. 2012). Coffee and caffeine beverage drinkers, consuming between 68mg/day and 509mg/day of caffeine, have been observed to report fewer depressive symptoms. On average, each cup of coffee reduced the risk of depression by 8 per cent (Wang et al. 2016). As a rough guide, a cup of coffee will contain approximately 100mg of caffeine. Uridine, DHA and choline

As we’ve seen above, the loss of neuronal plasticity, particularly in the hippocampal regions of the brain, is theorized to be a factor in depression. The human brain needs to have plasticity to be able to adapt to an ever-changing world – if it can’t, then depression may ensue (Duman & Li 2012). Three essential compounds that enable neuronal plasticity are uridine, the omega-3 fatty acid DHA (docosahexaenoic acid) and choline. Together, these nutrients can help provide the raw materials needed for neurite outgrowth (the formation of an axon or dendrite out from the cell body of a neuron) and synapse creation (synaptogenesis) (Wurtman 2014). Remember from the sections above that synaptic plasticity and neurogenesis both require mitochondria to provide the energy to build and maintain healthy neurons and synapses.

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30 Autism Spectrum Disorders

Autism spectrum disorders comprise a continuum of neurodevelopmental disorders, ranging from classical autism through to people with higher-functioning autism and Asperger’s syndrome. Individuals on the autism spectrum can display impairments in communication and speech and can exhibit poor social interaction and empathy (Palmieri & Persico 2010). It is now becoming apparent that mitochondria may play a significant role in the pathology of autism (Giulivi et al. 2010). It’s estimated that around 50 per cent of children with autism spectrum disorders will have biomarkers for mitochondrial dysfunction (Delhey et al. 2017). These biomarkers include lactate, alanine, acyl-carnitine, alanine-tolysine ratio, creatine kinase and aspartate transaminase (Frye 2012). What isn’t so clear is the exact ‘how, why and where’ of mitochondrial involvement. Is mitochondrial dysfunction a cause or a downstream effect of autism? Does mitochondrial dysfunction occur globally across autism, or only in certain subgroups? At first sight, it may seem a little worrying that the scientific community is struggling to find answers about mitochondrial involvement in autism. However, at least the questions are now being

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asked, and it’s quite an inspiration to see the scientific method of enquiry slowly unravel the answers.

Faulty brain development A developing young brain requires the rapid construction of neural components such as axons and dendrites to allow the outgrowth that a developing nervous system requires. Huge numbers of mitochondria are required to enable this process. Any undermining of mitochondrial function could therefore be potentially catastrophic for a child’s emerging central nervous system. An exploratory study examining mitochondrial abnormality in the lymphocytes of a small group of autistic children found four altered parameters (Giulivi et al. 2010): • low pyruvate dehydrogenase activity – possibly due to genetics, hormones or oxidative stress • impaired function of the mitochondrial electron transport chain – Complexes I and V were found to be the most compromised • raised levels of mitochondria-derived hydrogen peroxide • increased mitochondrial DNA irregularities.

Fever can cause regression in ASD patients with mitochondrial disease Mitochondrial disease is a group of named medical conditions which lead to disrupted adenosine triphosphate (ATP) production in mitochondria. Often there are nuclear or mitochondrial mutations associated with each disorder (Niyazov et al. 2016). The combination of fever and mitochondrial disease may greatly increase an individual’s chance of autistic regression. In a small retrospective study, around 70 per cent of autistic patients with mitochondrial disease were found to have regressed after fever. The results of this study suggest that extra care should be taken to control and manage fever in these patients (Shoffner et al. 2010). 260

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On average, 7 per cent of ASD patients suffer from overt mitochondrial disease, yet up to 80 per cent display symptoms of mitochondrial dysfunction (Frye & Rossignol 2011).

Key mitochondrial nutrients to consider in autism spectrum disorders There is a high likelihood that children with autism spectrum disorders will be given multi-vitamin and multi-mineral supplements by their parents. The problem is that many well-intentioned parents are now supplementing their children with an excess of some nutrients, whilst omitting the nutrients which are actually deficient (Stewart et al. 2015). Examination of the current literature and nutritional analysis are essential before supplementing children on the autism spectrum. One study found that autistic children are often over-supplemented with vitamin A, zinc and folate, while vitamin D, choline and calcium deficiencies go unnoticed (Stewart et al. 2015). However, before supplementing calcium, please be aware that excitotoxicity (see the section ‘Excitotoxicity’ in Chapter 11, ‘Calcium Storage and Regulation’) is implicated in autism (Essa et al. 2013). Dysregulated calcium homeostasis is part of the pathology of autism spectrum disorders and so it may be best to ensure sufficient dietary calcium rather than supplementing calcium (Breitenkamp et al. 2015; Palmieri et al. 2010). Mitochondria play an important role in regulating cellular calcium load. When cellular calcium levels increase, mitochondria tend to import high levels of calcium. Excitotoxicity occurs when glutamate-induced calcium entry into a neuron leads to neuronal mitochondria being overwhelmed with calcium. Once overwhelmed, mitochondria break down and trigger neuronal death (Lai et al. 2014). Practitioners need to consider optimizing magnesium status, reducing inflammation, avoiding long-chain saturated fatty acids (found in animal products and palm oil) and simple carbohydrates, and decreasing oxidative stress. All these factors can be supportive in maintaining cellular calcium balance.

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If considering supplementing calcium in ASD patients, it is recommended to test blood and urinary calcium before supplementing, and then at three-month intervals during supplementation (Gallagher et al. 2014). Glutamate status can best be assessed in autistic children using a plasma amino acids test10 (Ghanizadeh 2013). Urinary glutamate measured through an organic acids test is not usually representative of central nervous system glutamate. In fact, surprisingly, autistic children have been reported to display lower levels of urinary glutamate than expected (Yap et al. 2010). Omega-3 fatty acids

The omega-3 fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are incorporated into mitochondrial membrane phospholipids. This incorporation benefits mitochondria by raising their sensitivity to adenosine diphosphate (ADP) (and so increasing ATP in response) and by making them more resistant to damage from reactive oxygen species (ROS) (Herbst et al. 2014). Low levels of omega-3 fatty acids are frequently seen in children with autism spectrum disorders. Omega-3 fatty acids play an important role in suppressing inflammation in the central nervous system, so a deficiency in these fatty acids is likely to undermine a developing brain. Omega-3 fatty acids (as DHA) also assist in the regulation of synaptic plasticity, as discussed in Chapter 29, ‘Depression’. Again, synaptic plasticity is an essential process needed for a young brain to develop and learn (Madore et al. 2016). Supplementation with omega-3 fatty acids has been shown to be beneficial for autistic children in many studies. One small-scale study observed symptom improvements of at least 30 per cent in most of the participants (Belmaker & Meiri 2014). Imbalances in the gut microbiota have been reported in autistic children. Surprisingly, omega-3 fatty acids can exert a beneficial effect here as well. Omega-3 fatty acid supplementation shifts the microbiota

10 A plasma amino acids test is available from: UK – Regenerus Laboratories: www. regeneruslabs.com; US – Doctor’s Data: www.doctorsdata.com.

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balance away from inflammatory species toward the more beneficial Lactobacillus and Bifidobacterium bacterial species (Madore et al. 2016). Citicoline

Citicoline (also known as CDP-choline) helps to prevent the loss or breakdown of the mitochondrial phospholipid cardiolipin (Gareri et al. 2015). Cardiolipin forms part of the inner mitochondrial membrane and interacts with complexes of the electron transport chain to support ATP synthesis (Paradies et al. 2014). Adolescent boys with attention deficit hyperactivity disorder showed improved attentiveness, cognitive processing and reaction times, and reduced impulsiveness, when supplemented with citicoline for 28 days (McGlade et al. 2015). Vitamin D

Vitamin D is an important regulator of brain and immune system development during pregnancy and childhood. Vitamin D plays an important role in the whole of embryonic growth and acts to protect against apoptosis and oxidation. It is thought that vitamin D may protect mitochondria from injury. A study in laboratory animals found that vitamin D had a protective effect when mitochondria were placed under stress (Cannell & Grant 2013). Many autistic children are vitamin D deficient, with some estimates suggesting that deficiency numbers could be as high as almost 90 per cent in children with the condition (Bener et al. 2014). Due to the importance of vitamin D in the developing brain and immune system, mothers need to assess their vitamin D status throughout pregnancy, as well as in their offspring throughout childhood. Curcumin

Whilst vitamin D is deficient in mother and child in autism spectrum disorders, the opposite is true for the toxic plastics additive bisphenol A. Bisphenol A is found in water bottles, tinned food can linings and till receipts – until recently it was even found in baby food products! Bisphenol A is well known as an endocrine disruptor, but it is less well known for its toxicity in neural development (Tiwari et al. 2016) and

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as a cause of mitochondrial dysfunction (Kaur et al. 2014). Bisphenol A is extremely toxic to hippocampal neurons, slows down the growth and development of neural stem cells and accelerates neurodegeneration (Tiwari et al. 2016). It is advisable that pregnant mothers steer well clear of this toxic inhibitor of mitochondria and neuronal development. The polyphenol curcumin is an inhibitor of some of the damaging neuronal effects of bisphenol A (Tiwari et al. 2016). It’s fascinating that a natural phenolic compound can help ameliorate some of the negative effects of a toxic synthetic phenolic compound. B12, folate and carnitine

In preliminary studies, vitamin B12, folate and carnitine have all shown promise in improving mitochondrial function in autistic children (Delhey et al. 2017). In autistic children with mitochondrial disease, supplemental folate was found to be particularly important in supporting tricarboxylic acid cycle and electron transport chain integrity. The authors of the study theorize that the vital role folate plays in mitochondrial DNA synthesis may be a reason for folate’s significant effects (Delhey et al. 2017). Homocysteine, a risk factor for folate and B12 deficiency, is often found to be elevated in autism spectrum children, and is associated with poor communication skills (Puig-Alcaraz et al. 2015). It is possible, therefore, that correcting folate and B12 deficiencies may improve communication skills in these children.

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Final Word

The field of personalized nutrition aims to make sense of how an individual’s diet and lifestyle choices can translate into chronic health issues and disease. In this book I have explored how mitochondria, specifically, can provide a link between diet and its negative effects on the human body. Conversely, I have also explained how dietary and supplementary intervention can support mitochondrial function to optimize health and well-being. It is the dual role of mitochondria as energy providers (catabolic mode) or suppliers of cell components (anabolic mode) which underlies a large part of how diet translates into health or disease. Growth is always needed to heal wounds, repair tissue and build the armies of immune cells required to defend us against infection. However, we can certainly have too much growth. Unfortunately, the typical ‘Western’ diet, which is highly calorific and micronutrient sparse, pushes mitochondria too far into anabolic mode, turning on the glycolytic and lipogenic switches required for cell growth, proliferation and, potentially, chronic inflammatory disease. As explained in the preceding chapters, the good news is that there is an increasing amount of evidence to suggest that appropriate choices of diet, lifestyle and dietary supplements can go a long way to ameliorating the metabolic and biochemical damage caused by previous consumption of the ‘Western’ diet. Recent years have seen a quantum leap in our understanding of mitochondria, from their evolution to the ever-expanding role they play

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in health and disease. These mighty mitochondria continue to surprise us with their adaptability, resilience and seemingly endless abilities. Who would have thought that, size for size, the charge across mitochondrial membranes is almost equivalent to a bolt of lightning? It is mind boggling to think that these little ‘bolts of lightning’ are occurring across our literally trillions of mitochondria every second. We are often hugely impressed by the achievements of modern human engineering, but our ancient mitochondrial engineers were able to capture and harness sunlight energy many millions of years ago. Research today continues to reveal just how wonderful these microscopic mitochondrial engineers actually are. I hope that by revealing the considerable influence of mitochondria on health and disease, this book has offered practitioners new avenues for addressing a whole gamut of health conditions in their clients, and will enable nutritional and dietary interventions to be more finely tuned to meet individual needs. Thank you for your interest in this book and the multi-faceted world of mitochondria. I hope it has been both informative and entertaining!

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Appendix 1

Table of Fat Types Fat type

Typical carbon chain length

Saturation

Source

Short-chain fatty acid (SCFA)

2–5

Saturated

Gut fermentation of fibre, butter

Medium-chain fatty acid (MCFA)

6–12

Saturated

Coconut oil, avocado, MCT oil

Long-chain saturated fatty acid (LCFA)*

14–20

Saturated

16

Saturated

Coconut oil, palm oil, animal fat, cellular elongation of fatty acid

Very long-chain fatty acid (VLCFA)

22–34

Saturated

Cellular elongation of LCFA

Monounsaturated fatty acid (MUFA)

16–22

Monounsaturated

Olive oil, avocado, rape seed oil, animal fat

Polyunsaturated fatty acid (PUFA) Omega-3

16–24

Polyunsaturated

Fish oil, flax oil, algae oil

Polyunsaturated fatty acid (PUFA) Omega-6

18–24

Polyunsaturated

Vegetable oil, animal fat

* Palmitic acid is a common dietary and endogenous LCFA. Please note: Although PUFAs and MUFAs are also long-chain fatty acids, they have been put into their own categories to differentiate them from saturated fatty acid.

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Appendix 2

Nutrient Dosage Ranges from Research Studies The table below lists nutrients mentioned throughout the text, together with the range of dosages that have been used in research studies. It is included here as a starting point for practitioners when considering prescribing certain nutrients and is intended for information purposes only. Individual dosing recommendations have deliberately not been given because the dose that is right for any individual case will depend on the unique set of circumstances of that case, including current physiological levels, dietary intake levels, existing health conditions and body systems functioning and the aims and objectives of the intervention plan. The data has been compiled from the reference ranges of 1500+ studies considered in the researching of this book.

Supplement or nutrient

Approximate range of dosages (per day) used in the relevant research studies

α-Lipoic acid

300–1800mg

Ascorbate

75–1000mg

β-Glucans

1–3000mg There is a wide dosage range for β-glucans. Fungal-sourced β-glucans have a lower suggested dosage. Oat β-glucans are often recommended at multiple gram dosages.

Caffeine

Up to 400ml of coffee per day was found to protect against depression (Grosso et al. 2016). This is an average figure. Some people will have a lower tolerance for caffeine.

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Calcium

Aim to get calcium from dietary sources. If insufficient, supplement in small, divided doses to reach a combined dietary and supplemental total of between 1000mg and 1200mg. Please see ‘Calcium’ section in Chapter 27, ‘Osteoporosis’, for a discussion on calcium supplement safety.

Carnitine

1000–2000mg

Carnosic acid

Up to 750mg of rosemary leaf.

CDP-choline (citicoline)

500–1000mg; 250–500mg in adolescent males (McGlade et al. 2015).

Chilli (capsaicin)

Capsaicin cream (0.025–0.075%) applied up to 3 times daily for pain relief.

Chondroitin sulphate

800–2000mg

Cinnamon

Up to 120–6000mg (Costello et al. 2016). Considered safe in amounts found within food – a constituent cinnamaldehyde is considered unsafe when intake exceeds 700mcg.

Coenzyme Q10 (CoQ10)

30–300mg

Conjugated linoleic acid (CLA)

750–2000mg

Curcumin

500–4000mg As a polyphenol, curcumin will trigger antioxidant gene expression via hormesis. Please see Chapter 15, ‘Health, Toxicity and Hormesis’, for more information.

DHA (docosahexaenoic acid)

400–1000mg

EGCG (epigallo-catechin3-gallate)

200–600mg As a polyphenol, EGCG will trigger antioxidant gene expression via hormesis. Please see Chapter 15, ‘Health, Toxicity and Hormesis’, for more information.

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Supplement or nutrient

Approximate range of dosages (per day) used in the relevant research studies

EPA (eicosapentaenoic acid)

1000–2000mg

Folate (as 5-MTHF/5’methyltetrahydrofolate)

200–600mcg Synthetic folic acid is generally better absorbed than 5-MTHF. However, 5-MTHF can compensate for a polymorphism, which may negatively affect folate metabolism. The use of 5-MTHF lessens the chance of masking a vitamin B12 deficiency, compared to synthetic folic acid (Scaglione & Panzavolta 2014). Additionally, synthetic folate supplementation can lead to increased blood levels of unmetabolized folic acid. There are some concerns that unmetabolized folic acid may block or interfere with the activity of 5-MTHF (Smith et al. 2008).

Garlic extract

300–7000mg A wide variety of formulations are available.

Ginger

1000–2000mg

Glucosamine sulphate

1500–4500mg

Hawthorn fruit extracts (Crataegus)

160–1200mg

Hyaluronic acid

4–80mg

Magnesium

125–350mg Please note, doses of magnesium over 350mg may lead to transient diarrhoea and gastrointestinal discomfort. Research supports higher intakes of magnesium for some specific conditions – please see www. ncbi.nlm.nih.gov/pubmed.

Maitake mushroom

1000–1500mg

Mitoquinone (Mito Q)

5–20mg (Johnson & Grant 2015)

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NAD+ (as nicotinamide riboside)

125mg (dosage guidance of manufacturers) 250–1000mg of nicotinamide riboside has been supplemented in a study lasting 9 days. The study was an initial investigation into the possible benefits of nicotinamide riboside to support mitochondrial function (Airhart et al. 2017).

Naringenin

Naringenin is a flavonoid naturally present in grapefruit, oranges, bergamot and tomatoes. Naringenin is an inhibitor of liver detoxification enzymes and may therefore significantly alter the metabolism of many prescription drugs (Fuhr et al. 1993). For this reason, the high levels of this flavonoid used in animal studies are not recommended. A much lower dose of 500mg is suggested by supplement manufacturers. Naringenin is also present in much smaller amounts in citrus flavonoid complexes. Naringenin is a polyphenol and much of its beneficial action will be via its pro-oxidant properties, triggering the expression of endogenous antioxidants (de Oliveira et al. 2017). Please see Chapter 15, ‘Health, Toxicity and Hormesis’, for more information which explains how pro-oxidant plant compounds can be protective to mitochondria.

Niacinamide

14–30mg Higher doses used for some health conditions – please see www.ncbi.nlm.nih. gov/pubmed.

Pantethine

5–10mg Higher doses used for some health conditions – please see www.ncbi.nlm.nih. gov/pubmed.

Phospholipids

300–500mg as krill oil, for omega-3 phospholipid content. 500mg of krill oil contains 200mg of phospholipids.

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Supplement or nutrient

Approximate range of dosages (per day) used in the relevant research studies

Policosanols

2–20mg

Pomegranate

50–200ml of pomegranate juice The polyphenols within pomegranate will trigger antioxidant gene expression via hormesis. Please see Chapter 15, ‘Health, Toxicity and Hormesis’, for more information.

Pyridoxal 5’-Phosphate

1.3–80mg Higher doses used for some health conditions – please see www.ncbi.nlm.nih. gov/pubmed.

Red yeast rice

1000–5000mg

Resveratrol

10–200mg As a polyphenol, resveratrol will trigger antioxidant gene expression via hormesis. Please see Chapter 15, ‘Health, Toxicity and Hormesis’, for more information.

Riboflavin 5’-phosphate

1.1–25mg

Shiitake mushroom

6–16g, which equates to 6–8 mushrooms.

Soluble fibre

10.2–22g as blond psyllium for up to 8 weeks. Soluble fibre is present in many other foods and supplements. Some people may not tolerate psyllium very well.

Taurine

500–1000mg Higher doses used for some health conditions – please see www.ncbi.nlm.nih. gov/pubmed.

Thiamine

1–30mg

Uridine

500–1000mg (Kondo et al. 2011)

Vitamin A

3000–10,000IU

272

A ppendi x 2

Vitamin B12

2.4–500mcg Higher doses used for some health conditions – please see www.ncbi.nlm.nih. gov/pubmed.

Vitamin D

600–4000IU

Vitamin E (as mixed tocopherols)

15–600mg

Zinc

8–40mg Supplementary zinc may be contraindicated for Alzheimer’s and Parkinson’s disease patients (McCord & Aizenman 2014).

273

Glossary

α-proteobacteria  the bacterial ancestors of mitochondria

anterograde  movement away from the nucleus

β-cells  insulin-secreting cells in the pancreas

antigen  a toxin or other foreign substance that stimulates the immune system

β-oxidation  the breakdown of fat to provide energy in mitochondria acetylation  the addition of the acetyl part of acetyl-CoA to a protein, which alters its behaviour acetyl-CoA  a molecule that participates in the tricarboxylic acid (TCA) cycle, lipid synthesis, gene expression and protein modification adenosine triphosphate (ATP) the high-energy molecule (mainly produced by mitochondria) that powers our cellular processes adipokine  a type of fat (adipose tissue)-derived hormone anabolism  constructing molecules from smaller units in the cell antagonist  a substance that opposes or inhibits another substance or process

274

antioxidant response element a segment of deoxyribonucleic acid (DNA) which is activated by oxidative stress. Once activated, it enables the production of multiple antioxidant enzymes. apoptosis  programmed cell death apoptosome  a body formed when cytochrome c is released from mitochondria, which helps to orchestrate apoptosis archaea  a single-celled prokaryotic (without a nucleus or organelles) organism which became host to α-proteobacteria. The fusion or endosymbiosis of these two organisms enabled the evolution of all animals, plants and fungi. autophagy self-eating

Glossary

autoreactive T cell a T cell that triggers the body to produce an immune response against its own tissue bacteria  a single-celled prokaryotic (without a nucleus or organelles) organism B cell  a type of leukocyte which secretes antibodies calcium buffering  the control of cytosolic calcium levels to modulate calcium-dependent processes calcium wave  a momentary increase in cytosolic calcium succeeded by another momentary increase. The calcium waves formed can be restricted to one cell or occur across many cells simultaneously. carbon skeleton  the compound that remains after ammonia has been removed from an amino acid cardiomyocyte  adult cardiac muscle cell cardiomyopathy  disease of the heart muscle. There are several different categories of cardiomyopathy which alter heart function in a way that depends on the type of muscle affected. carnitine shuttle  a mechanism involving the transport of long-chain fatty acids across the mitochondrial membranes catabolism  breaking down molecules into smaller units to produce cellular energy

chondrocyte  cells that aggregate together to help form cartilage and the extracellular matrix cofactor  an organic compound or metal ion necessary for the function of an enzyme creatine  a protein-derived compound which is used (as part of phosphocreatine) to allow short, intense bursts of energy, particularly in muscle cyanobacteria  bacteria that obtain their energy through photosynthesis cytochrome a haeme-containing complex cytokine  a protein secreted by immune cells which allow cells to communicate with each other. Cytokines can be both pro- and antiinflammatory. cytoskeleton  a scaffold-like structure that gives a cell its unique shape and form cytosol  the aqueous component of the cytoplasm of a cell deoxyribonucleic acid (DNA) the molecule within a cell which contains the genetic code for an organism effector T cell a leukocyte that is important in both cell-mediated and adaptive immunity electron transport chain (ETC)  a series of complexes which releases energy from NADH and FADH2 to synthesize ATP endogenous  produced within the body

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endoplasmic reticulum (ER) an organelle which forms a network of tubes within the cell endosymbiosis  the fusion of archaea and bacteria to form eukaryotes enzyme complex  an enzyme unit formed from multiple protein subunits eukaryotes  organisms whose cells contain a nucleus and organelles excitotoxicity  damage to or destruction of neurons due to overstimulation by the neurotransmitter glutamate foam cells  cells formed from macrophages of the immune system that have entered the blood vessel wall glucogenic  describes amino acids that can be converted to glucose through gluconeogenesis gluconeogenesis  the generation of glucose from non-carbohydrate carbon substrates glutathione  an antioxidant glycolysis  a process that converts glucose into pyruvate haeme  an iron-containing complex which enables haemoglobin in blood cells to carry oxygen. Haeme is also a cofactor in cytochrome enzymes. hormesis  a term used for when a small amount of toxin elicits a larger beneficial response hypomethylation  a decrease in the epigenetic methylation of a gene, often leading to its over-expression

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hypotensive  lowering the blood pressure immune synapse  a synapse that allows exported mitochondrial adenosine triphosphate (ATP) and its metabolites (purines) to communicate with other lymphocytes immunometabolism  modifying the immune system by altering cellular and mitochondrial metabolism inflammasome  a multi-protein inflammatory complex that forms a major part of the innate immune system innate immune system  the part of the immune system that responds immediately to pathogens by recognizing the generic components of pathogens, rather than the specific species of bacteria ketoacidosis  an excessive build-up of ketones in the body ketogenic  forming or stimulating the production of ketones ketone  an organic compound containing a carbonyl group attached to two alkyl groups Krebs cycle  an alternative name for the tricarboxylic acid (TCA) cycle or citric acid cycle leptin  a type of adipokine involved in the control of appetite leukocyte  white blood cell macro-nutrients  a dietary component which comprises either carbohydrate, fat or protein macrophage a leukocyte that engulfs and digests microscopic bodies

Glossary

methylation  the addition of a methyl group (CH3) to a compound

necrosis  a type of cell death which stimulates an inflammatory response

microbiota  a community of up to 100 trillion microbial cells, held mainly within the gastrointestinal tract. This microbial community is largely bacteria, but also consists of yeast, archaea and viruses.

neuropathic pain  pain caused by aberrant signals within the nervous system

microglia  specialized immune cells which reside in the central nervous system micro-nutrients  vitamins and minerals microtubule  a ‘track’ along which a mitochondrion can move within a cell mitochondrial biogenesis the creation of brand-new mitochondria mitochondrial DNA (mtDNA)  DNA within mitochondria which help to encode several mitochondrial proteins mitochondrial membrane potential  the charge on the surface of a mitochondrion mitohormesis  hormesis in mitochondria mitophagy  autophagy of mitochondria mitosis  the process of deoxyribonucleic acid (DNA) division that allows a growing cell to divide. As more cells grow and divide, increased cell numbers lead to the growth of related tissue. Mitosis allows a parent or mother cell to divide into two daughter cells. motility mobility

neutrophil  a type of leukocyte associated with oxidative stress and inflammation nutraceutical  a food that is both a nutrient and a pharmaceutical osteoblast  a cell that builds bone osteoclast  a cell that breaks down bone outgrowth (in axons)  the process of constructing an axon out of the cell body of a neuron. Axon outgrowth is required for the growth and repair of neurons. over-nutrition  a form of malnutrition which can result from overconsumption of either macro- or micro-nutrients oxidation  the removal of highenergy electrons and hydrogen from a compound oxidative phosphorylation the oxidation of nutrients to produce adenosine triphosphate (ATP) palmitate  a long-chain saturated fatty acid associated with inflammation palmitoylation  the binding of palmitate to the amino acid cysteine phagocyte  a type of cell that can engulf and destroy pathogens

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phosphocreatine  a molecule used to accelerate energy delivery to the brain, retina, heart and muscle

renin–angiotensin system a mechanism that assists in the control of blood pressure

phospholipids  a group of lipids comprising two fatty acids, a phosphate group and glycerol. Phospholipids are important components of all cell membranes.

resveratrol  a substance produced by plants in response to injury or attack by pathogens, often used as a supplement

pregnenolone  a steroid that plays a main role in the production of all other steroid hormones, known as ‘the mother of steroid hormones’ prokaryotes  organisms whose cells do not contain organelles and a nucleus

retrograde  movement toward the nucleus substantia nigra  a structure in the midbrain that is important in reward and movement synthase  an enzyme that acts as a catalyst to help synthesize biological compounds

protein folding  a protein folding into a precise three-dimensional shape. Without the correct shape, many proteins have no function.

T lymphocyte/T cell a leukocyte that is important in cell-mediated immunity

purine  building blocks for DNA and substances that can be broken down to form uric acid

transcription factor  a cellular compound which passes information for gene transcription directly to the deoxyribonucleic acid (DNA)

pyruvate  a molecule created from glucose via glycolysis pyruvate dehydrogenase complex (PDC)  the largest enzyme complex in mammals reactive oxygen species (ROS)  unstable intermediates of oxygen metabolism. ROS provide essential cell signals at low levels, but in excess, cause oxidative stress reduction  the addition of highenergy electrons and hydrogen to a compound

278

tricarboxylic acid (TCA) cycle the first stage of aerobic respiration in mitochondria. The TCA oxidizes acetyl-CoA, in a step-by-step process, to reduce the electron donors NADH and FADH2 up-regulation  the increase in activity of a biological system in response to a stimulus vascular endothelium  blood vessel lining vasoconstriction  constriction of the blood vessels

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Subject Index

Note: figures and illustrations are indicated by page numbers in italics acetaldehyde 72 acetoacetate 81 acetone 81 acetyl-CoA actions within mitochondria and cell 67 alcohol 71–2 calories converted to 14 cholesterol synthesis 186, 190 conjugated linoleic acid 235 dietary strategies draining energy from 54 dual role 19–20 endogenous lipid synthesis 235 even-chain fatty acids 40 export from mitochondria 77–8, 89, 163, 186, 228, 235 fatty acid synthesis 136, 143, 190, 228 glycolytic switch 79 ketogenic amino acids 41 lipogenic switch 76 α-lipoic acid 71–2 liver 80–1, 85 low cellular insulin 82 as output of PDC 33–4 PGC1-α, mitochondrial biogenesis and acetylation 69–71 points for practitioners 72 protein acetylation 68–9, 72 Randle cycle 63–5 superoxide dismutase 170 TCA cycle 34–5 as vital energy source and cell controller 67 see also citrate

312

acetylation definition 68 excess 68–72 PGC1-α and mitochondrial biogenesis 69–71 protein 68–9, 72 relaxing chromatin 77–8 acetylcholine 214, 218, 221 acyl-carnitine 259 adenosine 160, 247 adenosine triphosphate (ATP) 37 AMPK 53–4 β-oxidation 39, 177 brain 17–18, 177 calcium 101–4, 178 calorie restriction decreasing 133 cardiac muscle contractions 154 cholesterol efflux 190 citicoline 218, 263 coenzyme Q10 182, 219 curcumin 219 cytochrome c 105–6, 112 definition 18 electron transport chain 36–8, 219 endosymbiosis 26–7 extracellular 86, 92–4, 160, 247 fusion protecting supply of 47 glucose, calcium and insulin 160 glycolytic switch 75, 79 HDL and LDL particles 154 heart 17–18, 73, 177, 180 inhibited axon growth 135 inhibiting PDC 63–4 insulin secretion 107, 160–1 intracellular 86, 93 ketones 84–5

lipid peroxides reducing synthesis 149–50 lipogenic switch 91 magnesium 109, 162, 180–1 maintaining supply of 43 mitochondria-dependent pump 138 mitochondria-depleted cells 46 mitochondria removal and replacement 204 mitochondrial anabolic transformation 75 mitochondrial delivery 45, 106 mitochondrial disease leading to disrupted production 260 mitochondrial dysfunction in gut epithelial cells 216 neurodegeneration 49 NSAIDS 238 omega-3 fatty acids 163, 262 organophosphates reducing synthesis 148 over-nutrition leading to decreased synthesis 18 oxidative phosphorylation 26, 31–2 pain 246–7 policosanols 192 production as aerobic process 129 soluble fibre 165 source of 30 static cardiac mitochondria 180 sunlight energy relay 32 switch from synthesis as strategy in cancer fight 43 synthase 36–8 T cells 87, 94

S ub j ect I nde x

transfer to creatine 99 use as extracellular immune system signal 92–4, 247 vitamin A 208 vitamin B12 and folate 98 whole body requiring energy in form of 43 adipic acid 157–8 adipocytes 152 adipokine 90–1, 191, 195–6, 238 adipose tissue 83, 91, 152, 159, 163, 165–6, 195–6, 256 adrenaline 171, 251–2 adrenodoxin 119 advanced glycation endproducts (AGEs) 237–8 Advanced NMR Lipids LipoProfile 154 aerobic glycolysis associated with inflammation and cancer 75–6, 113, 195 autoimmunity 196 calcium mishandling 244 fuel requirement of T cells 88 growth and wound healing 194–5 ketogenic diet 235 lupus 199 mitochondria implicated in 196–7, 226 multiple sclerosis 196–7 plant compounds 135 rapid proliferation of cells 75–6, 226 requirements 195 Th17 cells requiring 155, 196, 199 tumour cells gaining energy from 75, 84, 87 where cell chooses to rely on glycolysis for energy 195 aerobic respiration 26–7, 29, 32–4, 79 ageing 65, 69 alanine 259 alanine-to-lysine ratio 259 alcohol 71–2, 109–10, 120, 170, 242, 257 aldehyde dehydrogenase 252 ALDH2 179, 187 AlgaeCal 245 allicin 243 allostasis, maintaining ageing, metabolic syndrome and metabolic flexibility 65 flexibility of mitochondria necessary for 19, 62 points for practitioners 66 Randle cycle fuel choice 63–4 α-ketoglutarate 41, 226

α-lipoic acid 55, 66, 71–2, 162, 201 α-proteobacteria 24–6, 74, 254 α-tocopherol 206–7 Alzheimer’s disease acetylcholine loss 218, 221 activation of 12-lipoxygenase 145 amyloid β 104, 145, 211–12, 220 calcium 104, 212–13, 244 coenzyme Q10 219 as common type of neurodegenerative disease 211 curcumin 57 dysfunctional mitochondria 18 excessive apoptosis 130 excessive fission 49 haeme deficiency 115 impaired mitophagy 55 insulin resistance and type 2 diabetes 214 ketones 83 MAM-related pathology 108, 212–13 neuroprotectin in brain 219 PET scan 156–7 protein misfolding 104, 126, 145, 211–12 reduced activity of PDC 65 seeding 215 synaptic loss 218 tau proteins 57, 211, 217 taurine 220 tubulin problems 149 amino acids 31, 41, 87, 91, 98–9, 172–3, 181, 183, 257, 262 aminoglycosides 29, 254 ammonia 118–20 AMP-activated protein kinase (AMPK) calorie restriction 133–4 definition 51 helping reduce excessive fission 50–1 and insulin 54–5 in mitochondrial biogenesis 60, 70, 76 nurturing regeneration 53–4 PGC-1α 59–60 AMP-kinase 192 AMPK see AMP-activated protein kinase (AMPK) amylin 126, 214 anabolic mode 131–2, 150–1, 163, 226, 228, 233, 235, 265 anabolism 62–3, 73–9, 97 anaerobic respiration 32–3, 65, 74, 79

anaplerosis 226 angiotensin II 169, 175 antagonists 89, 102, 109–10, 181, 233 anterograde movement 56 anterograde signalling 125 anthocyanin 142, 231 anti-ageing proteins AMPK and NAD+ 134 conditions for working 69, 72 loss of activity in later life 170 method of working 72 resveratrol 137 SIRT1 59, 69–72, 76, 159, 166, 243, 254–5 SIRT3 51, 70–1 antibiotics 29, 38, 145, 254–5 antigens 86–7, 93–4 antioxidant response element (ARE) 122, 166–7, 179, 230 antioxidants ascorbate 110 cardiac 182 carnosine 252 endogenous 121–2, 135–6, 140, 231 excessive 45 glutathione 70 glutathione peroxidase and catalase 252–3 insufficient defences 48 inter-relationships 183 low levels of ROS 18 lupeol and curcumin 243 mitochondrial SOD 168 mitochondrial-targeted 197, 210 mitoquinone 49, 183, 210 NADPH quinone reductase 242 osteoarthritis 240 plant polyphenols 171, 200–1, 230–1 resveratrol 166–7 ROS quenching 95, 204 taurine 167, 181 ubiquinol and ubiquinone 183 vitamin C 46, 172, 258 apolipoprotein E, ApoE4 isoform 213 apoptosis arachidonic acid derivatives 138 β-cell 71 bone-building osteoblasts 243 calcium signals needed 101 cancer 21, 111–13, 130, 222–3, 227–30, 232, 234–6 cardiolipin 157 chrondocytes 238–9 as ‘clean’ cell death 111

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apoptosis cont. concept overcoming resistance 111–12 cytochrome c 105–6, 112, 227 death signals initiating 112 degenerative disease 112–13, 130 excessive fission 48–50 foods supporting mitochondria in triggering 231, 235–6 healthy cells rescuing 58 mechanism 112 mitochondrial role 111–12, 126, 130, 154, 227, 229 organophosphates 148 points for practitioners 113 as programmed cell death 18, 111 vitamin D 263 apoptosome 112, 227 arachidonic acid 138, 218 archaea 23–7, 29, 42, 74 arginine 98–9, 172 arterial calcification 244–5 arterial inflammation 187 ascorbate 110, 206–7 aspartate 226 aspartate transaminase 259 aspirin 146, 240 astaxanthin 99, 207 astrocytes 118 atherogenic LDL-C 186–7 atherosclerosis 170, 172, 188–90, 213 atherosclerotic plaque 185, 190 ATP see adenosine triphosphate (ATP) ATP-binding cassette (ABC) 138, 189 ATP-sensitive potassium channels (KATP) 107 ATPase 109, 181 autism spectrum disorders biomarkers for mitochondrial dysfunction 259 energy metabolism-related organic acids levels 158 excitotoxicity implicated in 105, 261 faulty brain development 260 fever 260–1 mitochondrial involvement 259–60 nutrients for 261–4 range of 259 autoimmune disease aerobic glycolysis 194–5 diet and lifestyle choices 194–5

314

Hashimoto’s thyroiditis 195–6 multiple sclerosis 196–8 nutrients for 200–1 rheumatoid arthritis 198–9 systemic lupus erythematosus 199–200 autoimmunity association with metabolic syndrome 150–1 Cyrex array 7 as screen for 149 diet and lifestyle choices 77, 194, 199–200 mitoquinone 198 naringenin 201 saturated fat driving 90 T cells 88, 90, 195–6, 198–200 autophagy 44, 51–3, 137 autoreactive T cells 89–91, 196 axons 17, 56, 106, 135–6, 144, 149, 180, 216–17, 220–1, 253, 258, 260 B cells 91–3 B lymphocytes 93–4 B vitamins 43, 66, 184, 249 bacteria in colon 233 as domain of life 23–4, 27 intestinal 136, 145–6, 165, 209, 216 killing by ROS 95–6 Lactobacillus and Bifidobacterium species 263 microbiota 42 over-reaction to 92 oxygen from early 123 quantum evolutionary leap 29 see also cyanobacteria beetroot 174–5 Benda, Carl 16 β-glucans cancer 231–2 type 2 diabetes and insulin resistance 168 betahydroxybutyrate (β-OHB) 81 betaine 99, 110 β-lactams 29 β-oxidation acetyl-CoA derived from 64–5 compromised by excess acetylation 70 definition 39 discovery 39 fasting and calorie restriction 68 fatty acids transported as esters 41

fatty acids undergoing several cycles of 40, 81 fuel requirement of T cells 88, 97 fused mitochondria 47 heart disease 177–9 high 77 insulin resistance 161–2, 164–5 markers 157 as mitochondrial energy process 34 multiple sclerosis 142–3 need for coenzyme A 41 omega-3 fatty acids 174, 191 as source of ATP for liver, heart and muscle 39 thyroid hormone T3 206 bile acids 185, 191–2, 235 bile metabolism 191–2 bioavailability 240 biomarkers and laboratory tests Advanced NMR Lipids LipoProfile 154 chest pain profile 154 Cyrex array 7 149 GI-MAP and gut permeability profile 155–6 GPL-TOX 148–9 HOMA insulin resistance calculator 152–3 Interleukin 17 155 metabolic syndrome 151–2 methylation panel 155 of mitochondrial dysfunction 150–8, 259 organic acid test 157–8 Oxidative Stress 2.0 149–50 PET scan 156–7 Phospholipase A2 (PLA2) 157 proinflammatory cytokine profile 155 waist-to-hip ratio and BMI (body mass index) 152 biopterin 171–3 biosynthesis 67, 76–7, 79, 226 bisphenol A 263–4 blood pressure see hypertension blood testing 81 body mass index (BMI) 152, 170, 196 bone see osteoporosis brain Alzheimer’s disease 219 ammonia 118 apolipoprotein E 213 and blood barrier 113, 201, 220 cancer 33 cinnamon 166

S ub j ect I nde x

creatine 98 dependent on wellfunctioning mitochondria 129 fatty acids 39 faulty development 260 half-life of mitochondria 52 high energy demands of body 17–18 hippocampal regions of 255, 258 hungry for oxygen 255 independent metabolism 119 inflammatory shifts 255 insulin resistance 214 ketones 81, 83 α-lipoic acid 201 microglia 201, 221 neuronal mitochondria 254–5 omega-3 fatty acids 262 Parkinson’s disease 216, 220 PET scan 156 premature ageing of 115 requiring energy in form of ATP 43, 177 seeding in 215 striatum 220 substantia nigra 112, 220 taurine 181, 220 testing compounds for effect on 57 traumatic injury 221 vitamin D 263 breast cancer 50, 188, 228–9, 235–6 breath testing 81 butyrate 42, 165 C-reactive protein 245 caffeine 83, 190, 258 calcium autism spectrum disorders 261–2 cytosolic 101, 106, 108, 145 DASH diet 139 depression 254, 256 excessive 48–9, 145–6, 162, 178, 248 excitotoxicity 103–6, 109–10, 247, 256, 261 ginger 249 from glucose to insulin secretion in pancreatic β-cells 160 and heart 102, 178, 181 homeostasis 108–10, 213, 261 and mitochondria 100–3, 101–2 neuronal signalling 250 organophosphates 148

osteoporosis 244–5 and pain 247, 250 as PDC activator 64 regulation 181, 212–13, 250 signals 100–1 storage and regulation 100–10 in T cell activation 94 as vital mineral 15 vitamin D 250 calcium buffering 102, 107–8 calcium wave 100–2, 178 calorie restriction 51, 54, 59–61, 66, 68–9, 72, 133–4, 166 cancer acetyl-CoA export 78 aerobic glycolysis 75, 84, 87, 113, 226 anaerobic respiration 33 apoptosis 21, 111–13, 130, 222–3, 227–30, 232, 234–6 brain 33 breast 50, 188, 228–9, 235–6 Cancer Act 1939 225 cell proliferation 14, 92, 222–4, 226–8, 230, 235 chemokine 228 chemotherapy 112, 224–5, 229–30, 235 citrate/acetyl-CoA export 78 citrate carrier 78 colon 33, 233, 235 curcumin 112–13, 225, 227–9 from evolutionary perspective 29 excess anabolism 74 excess protein acetylation 68 fatty acid synthesis 43 good/bad dichotomy 194 impact of diet 15, 78, 87, 131, 134, 145, 222–3 impact of nutrition 224–5 inflammation 112–13, 224, 227–8 insulin resistance 130 iron 116 ketones 84 lipogenic switch 87, 91–2 liver 235 lung 33, 122, 230 as metabolic disease 223–4 metabolic pathways 224 metastasis 50, 92, 224, 228, 236 mitochondrial involvement 222, 226 mutation theory 223–4 nutrients for 227–36, 248 ovarian 33, 229 pro-life-ration 74

prostate 91–2, 229, 235 reduced activity of PDC 65 risk factors for initiation 222–3 subtlety and co-operation to support patients with 255–6 TCA cycle 226 tunnelling nanotubes 58 vitamin B12 209 caproic 40 caprylic acid 40 capsaicin 248–9 carbohydrates acetyl-CoA 19 aerobic glycolysis 194–5 autoimmunity 90 avoiding simple 261 brand-new heart 177 calcium mishandling 244 carnitine 183 diabetes 14 excessive consumption 160, 237 fasting-mimicking diet 134 fuel choice 14, 19, 62–6 inflammatory shifts 255 ketogenic diet 133 ketone metabolism 80–2 low-GI diet 138–9 Mediterranean diet 97, 110 as source of oxidative stress 161 synthesis of ATP from 19 T cells 88, 199 Western diet 90, 113, 125, 131 carbon skeleton 41, 226 cardiac arrhythmia 178, 181 cardiolipin 96, 157, 208, 213, 218, 263 cardiomyocytes 57–8, 102, 151, 154, 177–84 cardiomyopathy 83–4, 177 cardiovascular disease 50, 62, 84, 172–3, 183, 188, 244 carnitine autism spectrum disorders 264 as carrier 81 as dietary riser 88 heart disease 183–4 shuttle 40 carnosic acid 191 cartilage 138, 237–40 catabolic mode 226, 265 catabolism 62, 73–4, 76–9, 96–7, 131 CDP-choline see citicoline cell blebbing 112 cell-mediated immunity 87–8

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cellular component synthesis aerobic glycolysis 75 catabolism and anabolism 73–4, 76–9 glycolytic switch 75–6 inflammation and proliferation 75–7 lipogenic switch 76 morphing mitochondria for cellular needs 74–6, 226 cellular energy catabolism 73 low 45, 53, 69–70 neurons relying on mitochondria for 55 cellular regeneration 113 cellular stress 46, 48 central nervous system (CNS) 43, 49, 65, 88–9, 144, 201, 221, 251, 255–6, 260, 262 chemokine 228 chemotherapy 112, 224–5, 229–30, 235 chest pain profile 154 chilli 248–9 cholesterol acetyl-CoA 77 cancer 235 damaged 185–6 essential for survival of all cells 185, 189 folate 172 glycolytic switch 79 high-density lipoprotein 137–8, 152, 154, 185, 190, 192 indicative of anabolic state 151 insulin resistance leading to raised 186–7 labels of ‘bad’ and ‘good’ 185 lipogenic switch 76 low-density lipoprotein 137, 152, 154, 175, 183, 185–7, 190–3 low-salt diet 175 MAM 212 mitochondria as starting point for synthesis 43, 186 mitochondria supporting clearance of products 187–8 mitochondrial role in metabolism 138 neurodegeneration 213 nutrients supporting metabolism of 189–93 oxysterols 151–2, 188–9 pregnenolone 119 problem of vulnerability 189 removal of meat from diet 137

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shelf life 185 statin drugs 182 synthesis 43, 137, 186, 195, 233 tissue and immune cells 129 triggering inflammatory signals 163 ubiquinol 183 cholesterol efflux 138, 188, 190 choline 208, 218, 258, 261 chondrocytes 238–40 chondroitin sulphate 239 chondroprotectives 239 chromatin 77–8 chronic fatigue syndrome (CFS) 65, 206 chronic pain mitochondrial involvement 246–7 nutrients for 247–50 sources 246 chylomicrons 81 cinnamon 166–7 citicoline 208, 217–18, 263 citrate 35, 40, 76–7, 79, 143, 155, 186, 190, 226, 233–4, 244, 248 see also acetyl-CoA citrate carrier (CIC) 78, 137, 186, 190, 228 citric acid 157–8 citric acid cycle see tricarboxylic acid (TCA) cycle CLA see conjugated linoleic acid (CLA) classification of organisms 24 co-operation endosymbiosis as theory of 28 genetic 27 supporting cancer patients 255–6 coconut oil 40, 90, 133 coenzyme A (CoA) 41, 64 coenzyme Q10 (CoQ10) autoimmune disease 200 in electron transport chain 36 fatigue 210 heart disease 182–3 hypertension 171 neurodegeneration 219 osteoarthritis 239 cofactors 151, 257 colon cancer 33, 233, 235 coloncytes 165 commuter train analogy 38 conjugated linoleic acid (CLA) 164, 235–6 CoQ10 see coenzyme Q10 Crataegus 182 creatine 98–9 creatine kinase 99, 259

Creutzfeldt-Jakob disease (CJD) 211, 215 CRP/hsCRP 151 curcumin autism spectrum disorders 263–4 cancer 112–13, 225, 227–9 catabolism 76 degenerative disease 113 diabetes 165, 167 healing and protective properties 164–5 mitochondrial motility in neurons 57 neurodegeneration 219 osteoarthritis 239 osteoporosis 243 suppression of IAP proteins 112 from turmeric 164, 225, 231 cyanobacteria 25–6 cyclooxygenase (COX) 233 Cyrex array 7 149 cysteine 91 cytochrome c 21, 36, 105–6, 112, 227 cytochrome enzymes 115, 167 cytokine definition 71 inflammatory 78, 95, 187, 216, 238–9 interferons as type of 95 interleukin 17 200 polarization of macrophages 187 proinflammatory profile 155 cytoskeletal tracks 17, 56, 106, 180, 253 cytoskeleton 55–7, 149, 214, 216–17, 219 cytosol 77–8, 99, 114, 118, 125, 186, 213 cytosolic calcium 101, 106, 108, 145 cytosolic citrate 226 damage-associated molecular patterns (DAMPs) 203, 208, 237 Darwin, Charles 28 DASH diet 139–40 Dawkins, Richard 29 demyelination 143 depression antibiotics 254–5 exercise 255 genetics 254 inflammation 255 leptin and metabolic syndrome 256

S ub j ect I nde x

mechanism 251–3 neurogenesis and nerve growth factor 253–4 neuronal signalling and calcium 254 neurotransmitters related to 251–2, 257 nutrients for 256–8 synaptic plasticity 253 diabetes activation of 12-lipoxygenase 139 folate 172 hydrogen sulphide 174 levels of ketones 82 levels of SOD activity 150 loss of calcium homeostasis 108 symptom of Friedreich’s ataxia 115 undermining lipid peroxide detoxification 179 see also type 1 diabetes; type 2 diabetes dietary excess see overnutrition dietary inflammatory index 131–2 diets calorie restriction 133–4 DASH 139–40 fasting-mimicking 134 Feingold 146–7 ketogenic 80–5, 89–91, 132–3, 235–6 low-FODMAP 140–1 low-GI (glycaemic index) 138–9 low-salt 175–6 Mediterranean 72, 76, 97, 110, 131, 135–7 MIND 141–2 modifying immune system 88–91 polyamine-reduced 145–6 supporting catabolism/ anabolism 76–7 Swank 142–4, 196 typical ‘Western’ 15, 70, 74, 77, 97, 125, 131, 143, 160, 265 use to alter mitochondrial behaviour 15, 131–2 using to modify immune system 88–91 vegetarian 137–8 vitamin K and green leafy vegetables 144–5 Wahls’ paleo diet 144 working at numerous different levels 147 diterpene 190–1

DNA (deoxyribonucleic acid) acetyl-CoA binding to 19 acetyl-CoA modifying 77–8 acetyl-CoA switching genes in 14 altered methylation 155 antioxidant response element 122, 167, 179, 230 building block for 92 cancer 223–4, 228, 234 division 46 fragmentation 112 hypomethylation 197, 201, 204–5 lower availability of SREBP 191 marker for oxidative damage to 150 mitochondrial call for help from 125–6 nuclear 16, 48, 59 redundant 27 retinoic acid acting through receptors 220 ROS activating damage 234, 252 synthesis and repair enzymes 115 transcription factors 59, 227 viral 95 see also mitochondrial DNA (mtDNA) docosahexanoic acid (DHA) 89–90, 92, 163, 174, 190, 199, 218–19, 232–4, 239–40, 258, 262 domains of life 23–5 DOPAL 252 dopamine 171, 217–20, 251–2, 257 dopamine-producing neurons 57, 108, 112, 220 dynein 56 dysfunctional mitochondria 18, 113, 148–9, 165, 170, 178, 203–4, 247 dyslipidaemia 83 dysmenorrhoea 249 early-life trauma 197, 199, 205 effector T cell 15, 86–8, 92–3, 198 eicosapentaenoic acid (EPA) 89–90, 163, 174, 199, 218–19, 232, 234, 239–40, 262 electron transport chain (ETC) 36 acetaldehyde extremely toxic to 72 aerobic glycolysis 195

body mass index 152 cardiolipin 208, 263 cell nucleus 125 coenzyme Q10 141, 171, 182–3 commuter train analogy 38 complexes 36 compromised by excess acetylation 70 cytochrome c 106, 112, 227 electron donors in 34–5 excess NADH 140, 161, 198 faulty brain development 260 folate 264 glucose 151 haeme 115 high blood glucose 138–9 hydroelectric dam analogy 37–8 hydrogen and electrons loaded into 79 hydroxytyrosol 135–6 iron-sulphur clusters 115 ketones 132 mtDNA encoding proteins 47 NADH and FADH2 34–6, 40 nitric oxide and peroxynitrite 103, 203 NSAIDS 238 organophosphates 148 osteoarthritis 238 oxidative phosphorylation in 35–8, 87 pain 247 Parkinson’s disease 217 pump analogy 35–7 stressed mitochondria 126 taurine 167, 206 ubiquinone and ubiquinol 36, 183 endoplasmic reticulum (ER) 102, 106–8, 110, 167, 212–13 endosymbiosis 25 cyanobacteria 25–6 evolutionary benefit of 26–8 from idea to acceptance 28–9, 111 oxygen as stimulus 123 process 26 symbiotic union 24–5 as theory of co-operation 28 endothelial nitric oxide synthase (eNOS) 91, 103, 169–74 endothelin 169 energy production in ageing bone 241 and bacterial infection 203 in cancer 50, 78 and catabolism 73, 76 in cells 32–4 central nervous system 251

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energy production cont. citicoline 218 effect of food colouring 147 entering TCA cycle 41–2 fatty acid and cholesterol synthesis 43 mitochondrial processes 34–41 points for practitioners 43 short bursts of 98–9 soluble fibre 42 sunlight energy from food 30–2 eNOS see endothelial nitric oxide synthase (eNOS) enzyme complex definition 36–7 PDC as 63, 183–4 epigallocatechin-3-gallate (EGCG) 76, 97, 122, 171, 200–1, 204, 231 epilepsy 83–5, 104–5, 132 equol 60 erythrocyte membrane 174 eukarya 23–5, 38 eukaryotes 23–9, 123 eukaryotic cells 25–6, 28–9 evolution cell 74, 224 domains of life 23–5 enabled by mitochondria 22–3 endosymbiosis 24–9 of mitochondria 25, 254 oxygen as stimulus 123 Plantae kingdom and oxidation event 25–6 points for practitioners 29 quantum leap in 29, 123 excessive calorie intake 38, 62, 67–70, 77, 79, 161–2, 166, 204, 215, 256 excessive fission 48–51 excitotoxicity 103–6, 109–10, 244, 247–8, 254, 256, 261 exercise AMPK 51, 54 β-cells and insulin target tissue 160 blood ketone levels 82 carnitine 184 catabolism and anabolism 76–7 demands on heart during 177 depression 255 eNOS 172–3 fatigue following 206 helping activate PDC 64 hormesis 124–5, 127, 179 inhibition of mitophagy and cellular regeneration 113

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insulin resistance 54 mitochondrial biogenesis 69–70 mitochondrial quality control 204 mitochondrial regeneration 13 relocation of PGC-α 59 ROS 46, 121–2, 170 shift to M2 macrophages 187 toxicity of free radicals 21 extra virgin olive oil 135–6, 164, 193 extracellular purine signalling 93 FADH2 see flavin adenine dinucleotide, reduced (FADH2) fasting 39, 63, 68, 70, 82–3, 134 fasting-mimicking diet 134 fatigue DNA hypomethylation 204–5 insulin resistance 204 low mitochondrial quality control 204 nutrients for 206–10 PAMPs, DAMPs and inflammation as cause of 202–3 thyroid 205–6 fatty acids acetyl-CoA 40, 63–5, 67–8, 77, 79 caffeine 83 carnitine 183 as dietary riser 88 endogenous 143 even-chain 39–40 free 48–9, 83 long-chain 65, 81, 88–90, 97, 133, 235–6, 261 medium-chain 40 mitochondria as starting point for synthesis 43 monounsaturated 39 odd-chain 39–40 omega-6 163, 207, 233 as phospholipid component 75 polyunsaturated 39, 41, 76, 92, 187 saturated 39–41, 76, 79, 81, 88–90, 186, 235–6, 261 see also palmitate short-chain 42, 88, 90, 155, 165 structures 39 switching with carbohydrate as fuel source 63–4, 66, 82

synthase 79, 228–9, 235 unsaturated 40 very long-chain 143 see also β-oxidation; omega-3 fatty acids Feingold, Benjamin 146 Feingold diet 146–7 ferritin 114 ferrochelatase 115 fever 260–1 fibre see soluble fibre fibromyalgia 210, 248–9 fission enabling mitochondrial quality-control check 48 excessive as problematic 48–9 protection against 50–1 as sometimes beneficial 49 and fusion 17, 44–7, 47, 50–1, 57, 119, 126 flavin adenine dinucleotide (FAD) 30–1, 35 flavin adenine dinucleotide, reduced (FADH2) 31, 34–6, 40, 161 foam cells 138, 185–90 FODMAP (low) diet 140–1 folate autism spectrum disorders 261, 264 cancer 209 depression 257 hypertension 171–3 role in methylation cycle 98 folic acid 99 food colouring 146–7 food processing and storage 188–9 frataxin 115 free radicals 18, 38, 169–70, 224 Friedreich’s ataxia 115–16 fruit and vegetables 76, 97, 122, 124, 127, 136, 140, 144, 230 fuel building 62–3, 79, 97 fuel burning 62–4, 73, 79, 96 fuel choice 14, 63–4, 66, 73–4 fuel delivery 62 fuel gauge 53, 67 fuel requirement of T cells 88 fuel sources 19, 54, 66, 82 fuel supply 62–3 fuel tanks 53–4 fusion and fission 17, 44–7, 47, 50–1, 57, 119, 126 garlic 141, 146, 243 Gas6 145 gene expression 18, 33, 68, 70, 76–7, 122, 151, 197, 203, 228

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genes depression 254 editing and growth 123 hypomethylation of 204–5, 209 mutated, in Parkinson’s disease 217 power of 16–17, 27–8 redundant 27 transfer of 16, 27 genetic co-operation 27 GI-diet (low glycaemic index diet) 138–9 GI Microbial Assay Plus (GIMAP) 155–6 ginger 190, 249 GLA matrix protein 245 glucagon 63 β-glucans cancer 231–2 type 2 diabetes and insulin resistance 168 glucogenic amino acids 41 gluconeogenesis 33, 41–2, 165 glucosamine 239 glucose and ATP synthesis 107 balance 60, 166, 168 brain use of 83 excessive intake 178, 214 fasting-mimicking diet 134 fatty acid cycle 63–5, 82 gluconeogenesis 33, 41–2 glycaemic index 138–9 glycolysis defect 198 HOMA Calculator 152–3 Mediterranean diet 136 pancreatic β-cells 160, 162 pyruvate created from 32 raised blood 48, 82, 138–9, 151, 174 SIRT1 activation 166 soluble fibre 165 steps to insulin secretion in pancreatic cells 160 suppression of mitochondrial retrograde response 125 transporter 198–9 in type 2 diabetes 49–50, 126 glucose transporter GLUT1 198–9 glutamate 104–5, 226, 256, 261–2 glutamate receptor 145–6, 247, 256 glutaminolysis 226 glutathione 70–1, 84, 145, 155, 172, 179, 183, 198, 215 glutathione peroxidase 46, 71, 122, 170, 252–3

glycaemic index (low) diet (GIdiet) 138–9 glycine 98 glycogen 63–4 glycolysis 32, 34, 74–5, 78–9, 84, 87, 91, 93, 113, 157, 162, 198, 234, 241 see also aerobic glycolysis glycolytic switch 74–6, 79, 87, 97, 195, 265 GPL-TOX (toxic environmental test) 148–9 Great Oxidation Event 25–6 green tea 61, 72, 122, 167, 171, 200–1 gut microbiota definition 42 effects of anti-inflammatory diet 76–7 low-FODMAP diet 140–1 mechanisms connecting to mitochondria 155 omega-3 fatty acids 262–3 ROS induction by PAMPS from 135 soluble fibre 165 gut permeability profile 155–6 haeme production 21, 114–17 half-life of mitochondria 52 Hashimoto’s thyroiditis 195–6 hawthorn fruit extracts 182 HbA1C (glycated haemoglobin) 151 HDL see high-density lipoprotein (HDL) cholesterol health 121–4, 126–7 heart β-oxidation of fatty acids 39, 177–8 and calcium 102, 178, 181 creatine 98 dependent on creatine 98 half-life of mitochondria 52 and insulin resistance 178–9 ketones 81 and mitochondria 179 pumping blood 177 relying on phosphocreatine 99 requiring energy in form of ATP 17–18, 43, 177, 180 heart disease calcium channel antagonists 110 calcium, insulin resistance and mitochondria 178–9 chest pain profile 154

disordered cholesterol metabolism 185 even and odd chains of fatty acids 40 excess protein acetylation 68 failing mitochondria 132 Friedreich’s ataxia 115 incomplete β-oxidation 177 insulin resistance 130 ketoacidosis 84 ketogenic diet 132 kissing and nanotunnels 179–80 loss of calcium homeostasis 108 low-salt diet 175 nutrients for 180–4 Helicobacter pylori infection 233–4 heptadecanoic acid 40 5-HIAL 252 high-density lipoprotein cholesterol (HDL-C) 137–8, 152, 154, 185, 190, 192 hippuric acid 157 HMG-CoA reductase 182, 186–7, 192–3 hod carrier analogy 35, 79 HOMA insulin resistance calculator 152–3, 153 homocysteine 173, 257, 264 hormesis 18, 123–7, 124, 171–2, 179, 200, 230 hormone synthesis 21, 119, 185 Huntingdon’s disease dysfunctional mitochondria 18 excessive fission 49 impaired mitophagy 55 hyaluronic acid 239 hydroelectric dam analogy 37–8, 37 hydrogen peroxide 71, 122, 252–3, 260 hydrogen sulphide 103, 173–4 4-hydroxy-2-nonenal (4-HNE) 187 4-hydroxybenzoic acid 157 27-hydroxycholesterol 188 hydroxyhexenal (HHE) 187 4-hydroxynonenal 138, 150 4-hydroxyphenylacetic acid 157 hydroxytyrosol 135–6, 164 hyperphosphorylation 57 hypertension DASH diet 139–40 low levels of SOD activity 150 mechanism 169–70 nutrients for 171–5 renin–angiotensin system 176 salt 175–6

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hypochlorous acid 245 hypomethylation 197, 201, 204–5, 209 hypotensive crisis 175 hypotensive effect 174 hypoxia inducible factor (HIF) 74 hydrogen sulphide 173–4 IAP (inhibitors of apoptosis) proteins 112 immune function, altering lipid rafts 91–2 mitochondria and innate immunity 94–6 mitochondrial ATP outside cell for immune synapse 92–4 points for practitioners 96–7 T cells 86–8 using diet and mitochondria 88–91 immune synapse 92–4, 94 immunoglobulin A (IgA) 94 immunoglobulin G (IgG) 94 immunoglobulin IgE 92 immunometabolism 194–200 inducible nitric oxide synthase (iNOS) 172, 205, 239 inflammasome complex 213, 249, 255 inflammasomes 95–6 inflammation acetyl-CoA 77–8, 163 aerobic glycolysis 75–6 anabolism 63, 74, 77 anaerobic respiration 32–3 autism spectrum disorders 261 cancer 112–13, 224, 227–8 catabolism 76 cellular stress 48 cinnamon 166 coenzyme Q10 239 curcumin 165, 230 DAMPs 237 depression 255 eNOS 172 excess calorie intake 67–8 excess misfolded proteins 126 excessive diet-driven 97 excessive effector T cell activity 87 excitotoxicity 104 fatigue 202–3 fatty acids 143 FODMAPs 140 green tea 200 hyaluronic acid 239 impact of Western diet 15

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leptin 196 leukocytes 50 lipid-induced 163 M2 macrophages 187 magnesium 109 MAM 212–13 microglial activation 221 mitochondrial dysfunction 96, 238 mitochondria’s vital role in 129, 255 naringenin 201 neurodegenerative disease 211, 213 neuroinflammation 145, 218–19 neutrophils 118–19 omega-3 fatty acids 92, 218–19, 255, 262 oxidative stress 161 pain 246 palmitate 40–1, 97 PAMPS 156 phospholipase A2 157 phospholipids 207 plant polyphenols 230 resolvins 234 resveratrol 243 ROS 199, 233–4 saturated fatty acids 89 SSRIs 255 toll-like receptors 233 toxicity 126 vitamin D 167 xanthine oxidase 170 inflammatory pain 246–7 innate immune system 20, 40, 92, 94–6, 141, 202–3, 206–9, 231–3 inner mitochondrial membrane (IMM) 16, 34, 36–7, 40, 157, 208, 218, 263 insulin and AMPK 54–5 balance with glucagon 63 fasting 152–3, 163 insulin resistance Alzheimer’s disease and Parkinson’s disease 214 amount of mitochondria 60 AMPK 54–5 causes 62, 159–60 consequences 63 depression 256 desensitizing PDC 65 displaying display MAMrelated pathology 108 eNOS 170 excess liver gluconeogenesis 42

fatigue 204 and heart 178–9 HOMA Calculator 152–3 increase in protein breakdown and gluconeogenesis 42 inhibition of mitophagy and cellular regeneration 113 leading to raised cholesterol and atherogenic LDL-C 186–7 levels of ketones 82 low-salt diet 175 and metabolic inflexibility 161–2 mitochondria implicated in 130, 150, 159–61, 168, 186, 256 non-pyruvate acetyl-CoA 65 nutrients reducing risk of 162–8 other conditions associated with 130 prevalence 159 production of excess fatty acids 43 steroid hormone synthesis 119 thyroid autoimmunity 195 toll-like receptors 233 undermining mitochondrial quality 204 insulin secretion 71, 82, 107, 109, 160–1, 160 insulin sensitivity 54–5, 82, 122, 152–3, 162–3, 166, 172, 179 interferons 95 Interleukin 17 155, 200 intestinal permeability 140, 155, 209, 216 iron 114, 116–17 iron-sulphur clusters 115–16, 119 isocitrate dehydrogenase 101 joints 237–40 ketoacidosis 82–4 ketogenic amino acids 41 ketogenic diets 80–5, 87, 89–91, 132–3, 235–6 α-ketoglutarate 41, 226 ketone metabolism 80–5 ketones brain usage 83 cancer 84 and disease 83–5 effect of caffeine 83 measuring 81

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organs metabolized by 80 supplementing 82 testing for 81 types of bodies 81 ketosis 64, 81–2, 133 kidneys ammonia 118–20 cancer 33 detoxification 118–20 diabetes-induced disease 84 as gluconeogenesis site 41–2 half-life of mitochondria 52 ketones 81 renin–angiotensin system 176 requiring energy in form of ATP 43 stones 83–4 synthesis of urea 118, 120 vitamin C 248 vitamin D 167 kinesin 56 kissing to heal cardiac mitochondria 179–80 for mitochondrial exchange of contents 58 Knoop, Georg Franz 39 Krebs cycle see tricarboxylic acid (TCA) cycle Krebs, Hans Adolf 35 L-DOPA therapy 220 laboratory tests see biomarkers and laboratory tests β-lactams 29 lactate 259 lactic acidosis 65 LDL see low-density lipoprotein (LDL) cholesterol leptin 90–1, 143, 195–6, 199, 256 leukocytes 50, 87, 92, 163 leukotrienes 138 lipid peroxides 71, 138, 149–50, 164, 179, 183, 187 lipid rafts 91–2, 97 Lipmann, Fritz Albert 35 lipogenic switch 75–6, 78–9, 87, 91–2, 97, 135–6, 151, 265 α-lipoic acid 55, 66, 71–2, 162, 201 lipopolysaccharide (LPS) 216 lipoprotein lipase activity 187 12-lipoxygenase 145 lipoxygenase (LOX) 233 liver ammonia 118–20 cancer 235 cholesterol synthesis 119, 190 cytochrome enzymes 167 detoxification 115, 117

disease 83, 118, 120 gluconeogenesis 41–2 half-life of mitochondria 52 hydrogen peroxide 71 inability to metabolize high levels of fat 20, 85 insulin resistance 43 LDL receptor 191 managing acetyl-CoA from fat 80–1, 85 producing ketone bodies 39 requiring energy in form of ATP 39, 43 SIRT1 activation 166 triglyceride build-up 71 urea synthesis 118–19 long-chain fatty acids (LCFAs) 65, 81, 88–90, 97, 133, 235–6, 261 low-density lipoprotein (LDL) cholesterol 137, 152, 154, 175, 183, 185–7, 190–3 low-GI (glycaemic index) diet 138–9 low-salt diet 175–6 lung cancer 33, 122, 230 lupeol 243 lupus 199–200 B lymphocytes 93–4 lysine 183, 259 lysosomes 52 macro-nutrients 19, 31, 36, 80, 178–9, 215 macrophages 163, 185–90, 216, 221, 242 ‘mad cow disease’ see Creutzfeldt-Jakob disease (CJD) magnesium as activator of PDC 64 analgesic property 145 calcium metabolism support 102, 109–10 chronic pain 247–8 depression 256 heart support 180–1 pancreatic β-cells 162–3 maitake mushrooms 232, 242 malondialdehyde (MDA) 71, 187 MAM see mitochondriaassociated ER membrane (MAM) maresin 218 Mediterranean diet 72, 76, 97, 110, 131, 135–7 medium-chain fatty acids (MCFAs) 40 medium-chain triglycerides (MCTs) 43, 81, 90, 97, 133

membrane signal disruption 232 metabolic acidosis 83–4 metabolic flexibility 14, 19, 65, 66 metabolic inflexibility 14, 62–3, 65, 161–2 metabolic syndrome acetyl-CoA and NADH 65 AMPK poorly expressed in 54 depression 256 excess protein acetylation 68, 71 insulin resistance as precursor to 130 α-lipoic acid 162 as metabolic inflexibility disease 62 omega-3 fatty acids 163 PDC 65 profile 151–2 struggle to select appropriate food sources 66 toll-like receptors 233 metformin 55 methionine 183 methylation 68, 98–9, 173, 197, 201, 204–5, 209 methylation panel 155 micro-nutrients 19, 194, 265 microbiota see gut microbiota microglia 201, 216, 221 microtubules 45, 55–7, 149 MIND diet 141–2 mitochondria and calcium 100–3, 101–2 calling for help 125–6 components 16 creating rapid bursts of energy 98–9 definition 16 derivation of name 16 dual role 265 dysfunctional 18, 113, 148–9, 165, 170, 178, 203–4, 247 evolution of 25, 254 flexibility 17, 19, 62 functions of 13–16, 19–21 gene power 16–17 as harvesters of sunlight energy from food 30–2 and heart 179 influence in disease 129–30 and innate immunity 94–6 like multi-fuel stove 62 morphing for cellular needs 74–6, 226 movement in cells 17 number in adult human 17 and osteoarthritis 238

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mitochondria cont. as starting point for internal fatty acid and cholesterol synthesis 43 using to modify immune system 88–91 mitochondria-associated ER membrane (MAM) 107–8, 212–14 mitochondrial antiviralsignalling protein (MAVS) 95 mitochondrial barrier 101 mitochondrial biogenesis 60, 70 adiponectin 151 AMPK in 60, 70, 76, 134 caffeine 258 cell nucleus 125 CLA 164 definition 48 dietary nitrates 103 fusion and fission cycle 47 ginger extract 190 hydroxytyrosol 135–6 ketogenic diet 84–5, 132 α-lipoic acid 71 mitochondrial dynamics 59–61 NAD+ 134 new mitochondria created by 17, 59, 178 oxysterols 188 PGC1-α and acetylation 69–70 policosanols 192 ROS triggering 121 SIRT expression 137, 255 SIRT1 166, 254 thyroid hormone T3 206 mitochondrial contagion 47–8 mitochondrial DNA (mtDNA) faulty brain development 260 folate 173, 257, 264 fused mitochondria 47 gene transfer 27 inflammatory response 96, 213 inheritance 17 α-lipoic acid 71 markers for disorders resulting from mutations 149–50 mitochondrial biogenesis 48, 59–60 need to remain inside mitochondria 96 neutrophils exporting 199 proteins encoded by 16 synthesis 264

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vulnerability to damage 126 mitochondrial dynamics autophagy and mitophagy 51–3 biogenesis 59–61 breast cancer 50 excessive fission 48 forming web of interconnected organelles 44 fusion and fission 45–8 half-life 52 kissing, nanotunnelling and tunnelling nanotubes 57–8 mitophagy as neuroprotective 55 motility 55–7 neurodegeneration 49 nurturing regeneration 53–5 points for practitioners 61 protection against excessive fission 50–1 quality control-check 48 shelf life 44, 52, 204 type 2 diabetes 49–50 mitochondrial function antioxidant compounds 167 autism spectrum disorders 264 brain development 260 cardiolipin 208 dietary nitrates 103 dietary supplements 162, 265 diets to support 84–5, 131–47 excess peroxynitrite 38 excess protein acetylation 68 laboratory tests and biomarkers related to 148–58 leptin 196 α-lipoic acid 201 misfolded proteins 211 nitric oxide synthesis 103 PAMPs and DAMPs 203 restoring PGC-1α to normal levels 60 Rooibos tea 55 superoxide dismutase 241 thyroid hormone T3 208 mitochondrial intermembrane space 16, 35–8, 99 mitochondrial matrix 16, 34, 36–8 mitochondrial membrane potential 48, 109, 266 mitochondrial permeability transition pore (mPTP) 105–6

mitochondrial pyruvate carrier (MPC) 33–4 mitochondrial regeneration 13, 45, 53–4, 113, 125 mitochondrial unfolded protein response 125–6 mitohormesis 124–5 mitophagy 51–3 acting as quality-control process 17, 45, 203–4 definition 44–5 factors leading to inhibition of 113 ketogenesis 85 as neuroprotective 55 removing worn-out or damaged mitochondria 47, 134 resistance to concept 111 ROS triggering 121 mitoquinone 49, 183, 198, 210 mitosis definition 46 neurons 55 monacolin K 193 monoamine metabolism 252–3 monoamine oxidase 252 monounsaturated fatty acid (MUFA) 39, 89, 110 motility (mitochondrial) 55–7, 56, 106, 214 MPC see mitochondrial pyruvate carrier (MPC) mtDNA see mitochondrial DNA (mtDNA) multiple sclerosis as autoimmune disease 196–8 impact of diet 15, 90 nutrients for 200–1, 205 Swank diet 89, 142–3 as T cell-mediated disease 88 Wahl’s paleo diet 144 muscles cardiac 57, 65, 154, 181 creatine 98 energy metabolism 201 ketones 81 requiring energy in form of ATP 43 mushrooms 110, 231–2, 242 mutation theory 223–5 myelin sheath 88, 144–5 N-methyl-D-aspartate (NMDA) receptors 104–5, 145, 247–8 NAD+ see nicotinamide adenine dinucleotide: oxidized (NAD+)

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NADH see nicotinamide adenine dinucleotide: reduced (NADH) NADPH see nicotinamide adenine dinucleotide: phosphate reduced (NADPH) nanotunnelling 57–8, 179–80 naringenin 171, 201 natural killer cells 232 necrosis 103–4, 111 negative ions 122–4 nerve growth factor (NGF) 135–6, 253–4 nerve regeneration 220 neurodegeneration calcium homeostasis 108 calcium regulation 212–13 cholesterol 213 Creutzfeldt-Jakob disease (CJD) 215 excessive cell death 14 excitotoxicity 104–5 inflammation 213 insulin resistance and type 2 diabetes 214 ketogenic diet 132 MAM 212–14 misfolded proteins and disease 211–12 mitochondrial dynamics 49 mitochondrial mechanics 214 mitophagy protecting against 55 and motility 106 nutrients for 217–21 olive oil polyphenols 135 Parkinson’s disease and mitochondria 217 Parkinson’s disease starting in gut 216 PET scan 156 reductive stress 214–15 seeding 215 tau proteins for neuron structure and energy supply 216–17 vitamin K 141, 145 neurogenesis 253–4, 258 neuroinflammation 145, 218–19 neuronal signalling 254 neurons 49, 51, 55–8, 104–6, 112–13, 130, 135–6, 144–5, 149, 179–80, 216–21, 248–9, 254, 264 neuropathic pain 93, 246–8 neuroprotectin 218–19 neurotransmitters 100, 104–5, 214, 218, 221, 251–2, 257 neurotrophins 135–6

neutrophil extracellular trap (NET) 199, 245 neutrophil to lymphocyte ratio (NLR) 245 neutrophils 118–19, 199, 206, 245 NF-kappa B 227–30, 243 nicotinamide adenine dinucleotide oxidized (NAD+) 30–1, 35–6, 63–5, 69–70, 72, 79, 133–4, 166 phosphate reduced (NADPH) 79, 198, 242 phosphate reduced oxidase (NOX) 169–70 reduced (NADH) 31, 34–6, 40, 53–4, 63–5, 69–70, 72, 78–9, 133, 140, 161–2, 166, 198, 210, 215 nicotinamide riboside 126, 166 nitric oxide 38, 78, 103–5, 145, 169, 172, 174, 203, 205, 209, 238–9, 247, 249 nitrosative stress 238, 252 non-HDL cholesterol 152 non-steroidal antiinflammatory drugs (NSAIDS) 238, 240 noradrenaline 171, 218, 251–2 NOX see nicotinamide adenine dinucleotide: phosphate reduced oxidase (NOX) Nrfs see nuclear respiratory factors (Nrfs) NSAIDS see non-steroidal anti-inflammatory drugs (NSAIDS) nuclear respiratory factors (Nrfs) 59, 166–7, 179 nutraceutical 193 obesity 14, 33, 42, 74, 132, 161, 179, 187, 195–6, 223–4, 238, 256 oestrogen 241 8-OHdG 149–50 oligodendrocytes 144–5 oligomeric proanthocyanidins (OPCs) 171 olive oil see extra virgin olive oil omega-3 fatty acids autism spectrum disorders 262–3 cancer 232–5 cholesterol metabolism 190–1 fatigue 207 healthy activity of acetylCoA 72

hypertension 174 immune system 92 Mediterranean diet 97, 137 neurodegeneration 218–19 osteoarthritis 239–40 supporting catabolism 76 type 2 diabetes and insulin resistance 163–4 omega-6 fatty acids 163, 207, 233 orchestra analogy 100–2, 104 organic acids test 157–8 organisms allowing retrograde response 125 classification of 24 endosymbiosis 24–5, 123 first appearing on Earth 23 in Great Oxidation Event 26 and quantum leap in evolution 123 types of 23–4 organophosphates 148 ossein-hydroxyapatite 245 osteoarthritis immune system involved in 237 insulin resistance 130 low levels of SOD activity 150, 241 mechanism 237–8 and mitochondria 238 nutrients for 239–40 pain relief 138 osteoblasts 242–3, 245 osteoclasts 242–3, 245 osteoporosis ageing bone 241–2 nutrients for 242–5 occurrence 242 use of Tamoxifen 242 outer mitochondrial membrane (OMM) 16, 34, 252 outgrowth (in axons) 221 ovarian cancer 33, 229 over-nutrition 18–19, 52, 70, 159–61, 178 oxaloacetate 41, 80, 82, 226 oxidation definition 31 evolutionary event 25–6, 123 of fatty acids see β-oxidation LDL-C vulnerable to 187 of nutrients to produce ATP 32 protection of cholesterol from 186 vitamin D protecting against 263

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β-oxidation acetyl-CoA derived from 64–5 compromised by excess acetylation 70 definition 39 discovery 39 fasting and calorie restriction 68 fatty acids transported as esters 41 fatty acids undergoing several cycles of 40, 81 fuel requirement of T cells 88, 97 fused mitochondria 47 heart disease 177–9 high 77 insulin resistance 161–2, 164–5 markers 157 as mitochondrial energy process 34 multiple sclerosis 142–3 need for coenzyme A 41 omega-3 fatty acids 174, 191 as source of ATP for liver, heart and muscle 39 thyroid hormone T3 206 oxidative phosphorylation (OXPHOS) aerobic respiration as 26 anti-inflammatory M2 macrophages 187 chronic psychological stress 252 drug inhibiting 55 within electron transport chain 35–8 fused mitochondria providing stable 47 glycolytic switch 75 insulin resistance 161 ketones 84 as mitochondrial energy process 34 sunlight energy from food 31–3 T cells 86–8 thyroid hormone T3 206 oxidative stress Alzheimer’s disease and Parkinson’s disease 211 antioxidant response element 167 astaxanthin 110, 207 within bone 243 calcium mishandling 244 as cause of mitochondrial dysfunction 178 cellular calcium balance 261 cinnamon 166

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eNOS 172 excess reductive stress leading to 162, 198 folate need 173 Friedreich’s ataxia 116 krill oil 207 low pyruvate dehydrogenase activity 260 misfolded proteins 126, 215 mitochondrion’s use of oxygen 26 monoamine oxidase 252 neutrophils 118–19 sources of 161 tetrahydrobiopterin 257 vegetarian diet 137 xanthine oxidase 170 Oxidative Stress 2.0 149–50 oxidized LDL (oxLDL) 185, 187, 193 oxoglutarate dehydrogenase 101 2-oxoglutaric acid 157–8 oxygen 24, 26, 32, 38, 74–5, 123, 255 oxysterols 138, 151–2, 188–9 pain chest pain profile 154 chronic 246–50 inflammatory pain 246–7 neuropathic 93, 246–8 relief for osteoarthritis sufferers 138 palmitate 40–1, 79, 90–2, 97, 106, 109, 162, 207, 228–9, 235–6 palmitic acid 40 palmitoylation 91–2, 228–9, 236 PAMPs see pathogen-associated molecular patterns (PAMPs) pancreatic β-cells 49–50, 93, 107, 110, 159–63, 160, 165 pancreatic islets 70, 126 pantothenic acid 41 paraquat 38, 242 parkin 168 Parkinson’s disease activation of 12-lipoxygenase 145 bilberry, blueberry and cranberry 142 coenzyme Q10 219 as common type of neurodegenerative disease 211 disorganized networks of microtubules 57 dopamine loss 218, 252

dysfunctional mitochondria 18 excess palmitate in lipid raft 92 excessive apoptosis 112–13, 130 excessive fission 49 in gut 216 impaired mitophagy 55 insulin resistance and type 2 diabetes 214 L-DOPA therapy 220 ‘MAM hypothesis’ of 108, 212 microglial activation 221 and mitochondria 217 mitochondrial contagion 47 PET scan 156–7 poor calcium regulation 212–13, 244 protein misfolding 126, 211–12, 214–15 seeding 215 synaptic loss 218 α-synuclein 108, 211–12, 214, 216 taurine 220 pathogen-associated molecular patterns (PAMPs) activation of toll-like receptors 141 bread and cereals 136 as cause of fatigue 202–3 fungal β-glucans 231 GI-MAP and gut permeability 155–6 plant compounds 135 vitamin D 208 pathogens 86–7, 94–7, 172, 187, 203, 233–4, 242 PDC see pyruvate dehydrogenase complex (PDC) pentose phosphate pathway 198 peroxisome proliferatoractivated receptor-γ (PPARγ) 59, 234 peroxisome proliferatoractivated receptors (PPARs) 59, 234 peroxisomes 143 peroxynitrite 38, 103, 209, 247, 249 PET scan 156–7 PGC-1α 59–60, 60, 69–70, 151, 258 phagocytes 95–6 phosphocreatine 98–9, 99 phospholipase A2 (PLA2) 157, 218 phospholipases 157

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phospholipids 40, 75, 96, 157, 163, 207–8, 217–18, 262–3 photosynthesis 26, 30–2 phylloquinone 141 plant compounds 122, 135, 167, 230 plant polyphenols autoimmune disease 200–1 cancer 230–1 cholesterol metabolism 189–90 hypertension 171 pro-oxidant properties 136 Plantae kingdom in eukarya domain of life 24 eukaryotic cells as building blocks 25 and Great Oxidation Event 25–6 policosanols 192 polyamine-reduced diet 145–6 polyamines 145–6 polysaccharides 231, 238–9, 242 polyunsaturated fatty acid (PUFA) 39, 41, 76, 78, 89–90, 92, 110, 187 pomegranate cancer 231 cholesterol efflux 190 hypertension 173 post-translational protein modification 68 potassium channel 107, 160 power per gene 16–17, 28 power station analogy 75–6, 226 practitioner points acetyl-CoA 72 altering immune function 96–7 apoptosis 113 calcium 110 energy production 43 evolution 29 haeme production 117 health, toxicity and hormesis 127 ketone metabolism 85 kidney detoxification and hormone synthesis 119–20 maintaining allostasis 66 mitochondrial dynamics 61 rapid bursts of energy 99 pregnenolone 21, 119 prion proteins 211, 215 pro-resolving lipid mediators 218–19 proinflammatory cytokine profile 155 proinflammatory cytokines 155 prokaryotes 23–4, 27–8

proliferation acetyl-CoA 78 acetylation 77–8 aerobic glycolysis 75–6 anabolism 63, 73 anaerobic respiration 32–3 autoimmune T cells 195 cancer cell 14, 92, 222–4, 226–8, 230, 235 lipogenic switch 76, 91, 265 mitochondria’s vital role in 129 pro-life-ration 74 propionate 42, 165 propionyl-Lcarnitine 184 prostaglandins 78, 138 prostate cancer 91–2, 229, 235 protectin 218 protein breakdown 42 protein folding 107–8, 125–6, 215 protein misfolding 104, 106, 108–9, 125–6, 145, 211–16, 220, 244 protein modification 40, 68 protein motors 17, 45, 56, 106, 214 proteinopathies 211–12 α-proteobacteria 24–6, 74, 254 punicalagin 173 purine nucleotides 170 purine receptors 93–4, 160, 247 pyridoxal 5’-phosphate (PLP) 249 pyruvate 32–5, 63–5, 79 pyruvate dehydrogenase complex (PDC) 33–4, 63–5, 71, 77, 82, 183–4, 249 quality control 17, 45, 48, 53–5, 125–6, 204, 217 quercetin 122 quinolones 29 quinone reductase (NAPDH) 242 radon gas 122 Randle cycle 14, 63–6, 64, 82 reactive oxygen species (ROS) 96 activating inflammatory responses 234 allicin 243 arachidonic acid 138 cardiac arrhythmia 181 cellular regeneration 113 cellular stress 48 citrate carrier 78 coenzyme Q10 171, 198, 200, 219

CRP 151 curcumin 164 definition 18 depression 251–3 drug leading to increased 55 dysfunctional mitochondria 45 excessive calorie intake 161–2, 204 excessive fission 48 exercise 46, 121–2, 170, 172, 179, 204 for fighting pathogens 96 glucose 151 high blood glucose 138–9 hormesis 124, 127 hyaluronic acid 239 hydrogen sulphide 174 hypertension 140 and immunity 95, 203, 208 infections 203 inflammasome 95 innate immune system 20, 96, 203, 208 insulin resistance 162, 178, 204 lipopolysaccharide and microglia 216 lupus 199 mitochondria as main source of 18, 45, 86, 161 mitochondria vulnerable to excessive 45 mitochondrion’s use of oxygen 26 mitohormesis 124–5 nitric oxide or peroxynitrite 103 NSAIDS 238 omega-3 fatty acids 262 pain 246–7 PAMPS 136, 155, 202 Parkinson’s disease 216–17 plant compounds 122, 135 plant polyphenols 171 pomegranate 173 proinflammatory cytokines 154 rheumatoid arthritis 198 SIRT3 inhibition increasing 70–1 smoking 170 in stomach 234 toll-like receptors 233–4 triggering mitophagy and biogenesis 121 vitamin C 172, 258 xanthine oxidase 170, 172 receptor activator of NF-kappa B ligand (RANKL) 243

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receptor for advanced glycation end-products (RAGE) 237–9 red yeast rice 193 reduction 31 reductive stress 161–2, 198, 214–15, 244 regeneration see mitochondrial regeneration renin–angiotensin system 175–6 resolvins 218, 234 respiration see aerobic respiration; anaerobic respiration resveratrol alcohol consumption 72 healthy activity of acetylCoA 72 insulin resistance and type 2 diabetes 166–7 in Mediterranean diet 137 osteoporosis 243 SIRT3 60 supporting catabolism 76 synergistic actions 60 unfolded protein response 126 retinoic acid see Vitamin A retrograde movement 56 retrograde response 125 rheumatoid arthritis 198–200 Rooibos tea 55 ROS see reactive oxygen species (ROS) rotenone 38, 217 salt 175–6 sarcoplasmic reticulum 178, 181 saturated fatty acids 39–41, 76, 79, 81, 88–90, 186, 235–6, 261 see also palmitate saturated fatty acids (SFAs) 40–1 seeding 215 selective oestrogen receptor modifier (SERM) 229 selective serotonin reuptake inhibitors (SSRIs) 255, 257 serotonin 171, 251–2, 255, 257 shiitake mushrooms 232, 242 short-chain fatty acids (SCFAs) 42, 88, 90, 155, 165 SIRT1 and SIRT3 see antiageing proteins smoking 122, 170, 230 SOD see superoxide dismutase (SOD) sodium 175–6

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soluble fibre 42, 84, 165 somatic mutation theory (SMT) 223–4 SREBPs 191 SSRIs see selective serotonin reuptake inhibitors (SSRIs) statin drugs 182, 192–3 steroid hormone synthesis 21, 119, 185 sterol regulatory elementbinding proteins (SREBPs) 186–7, 191 suberic acid 157–8 substantia nigra 112, 219–20 sulforaphane 167 sunlight energy electron transport chain 36–7 importance of water 31–2 from plant photosynthesis 30–2 relay race 31–2, 32 superoxide in blood vessels 175 in commuter train analogy 38 excess mitochondrial calcium increasing 146 hypertensive 172 mitochondrial biopterin 172–3 mitochondrial quality 204 oxidative stress in bone 243 oxygen radical 161, 169 production by dysfunctional mitochondria 170 production by NOX 169–70 proinflammatory cytokines 154 quercetin increasing 122 scavengers 183, 242 superoxide dismutase (SOD) 46, 70–1, 122–3, 149–50, 168, 170, 241–3 Swank diet 89, 142–4, 196 synaptic loss 218 synaptic mitochondria 49, 218 synaptic plasticity 253, 258, 262 synthase ATP 36–8 citrate 35 definition 35 endothelial nitric oxide 91, 103, 169–74 fatty acid 79, 228–9, 235 inducible nitric oxide 172, 205, 239 neuronal nitric oxide 105 nitric oxide 103 systemic lupus erythematosus 199–200

T cells (T lymphocyte) altering immune function 86–94, 97 autoimmune disease 195–201 autoreactive 89–91, 196 cytotoxic 227 definition 87 dependent on wellfunctioning mitochondria 129 effector 15, 86–8, 92–3, 198 fuel requirements 88 naïve 86–8, 198 quiescent 15 regulatory 87–90, 97, 143, 196, 198–201 Th1 87–8, 90 Th2 87–8 Th17 87–90, 143, 150, 155, 196, 198–200 types of 88 Tamoxifen 229, 240, 242 tau proteins 57, 216–17, 219 taurine cholesterol metabolism 191–2 diabetic complications 167 fatigue 206 healthy supply of ATP 43 heart disease 181 hypertension 173–4 osteoporosis 245 Parkinson’s disease and Alzheimer’s disease 220 TCA cycle see tricarboxylic acid (TCA) cycle tetrahydrobiopterin (BH4) 257 thiamine 184 thymic involution 197 thymus gland 86, 197–8 thyroglobulin (Tg) 195 thyroid hormone T3 205, 208 thyroid hormones 205–6, 208–9 thyroperoxidase (TPO) 195 tiredness see fatigue α-tocopherol 206–7 toll-like receptors (TLRs) 89, 91, 96, 141, 202–3, 206–8, 233–4 toxicity 121–4, 126–7 transcription factor of activated mitochondria (TFAM) 59–60 transcription factors 59, 78, 89, 95, 166, 179, 227–30 tricarboxylic acid (TCA) cycle alternative ways into 41 calcium 101 cancer, obesity and type 2 diabetes 226

S ub j ect I nde x

citric acid’s choice 43 definition 33 folate for supporting integrity 264 glycolytic switch 79 iron-sulphur clusters 115 materials required to kickstart 34 mechanism 34 as mitochondrial energy process 34 NADH and FADH2 36, 40, 161 organic acid tests 157 process 35 triglycerides 43, 71, 81, 90, 97, 133, 151, 191–2 tryptophan hydroxylase 257 tubulins 149 tumour necrosis factor receptor-associated factor 6 (TRAF6) 96 tumour suppressor protein p53 229 tunnelling nanotubes (TNTs) 58, 180 turmeric 164, 225, 231 type 1 diabetes disease of metabolic inflexibility 14 excess catabolism 74 ketoacidosis 82–4 type 2 diabetes Alzheimer’s disease and Parkinson’s disease 214 AMPK expression 54 butyrate and propionate 42 and cancer 223–4 causes 159–60 diet high in high-GI carbohydrate foods 139 dietary excesses 226 disease of metabolic inflexibility 14, 62, 66 enzymes in fatty acid synthesis 43 excess acetylation 68, 71 excess anabolism 74 excess calcium 110 excess liver gluconeogenesis 42 extracellular ATP to control insulin synthesis 160 heptadecanoic acid 40 HOMA Calculator 153 increase in protein breakdown and gluconeogenesis 42

ketoacidosis 82–4 ketogenic diet 132 Mediterranean diet 135 mitochondria implicated in 130–1, 150, 159–60, 168 mitochondrial fusion and fission 49–50 nutrients reducing risk of 162–8 8-OHdG levels 150 poor insulin secretion 161 prevalence 159 protein misfolding 126, 211, 214 SIRT3 expression 71 toll-like receptors 233 up-regulated MPC expression 33 tyrosine hydroxylase 252, 257 ubiquinol 36, 182–3, 210 ubiquinone 36, 141, 182–3, 210 ‘uncoupling’ proteins 37–8 up-regulation 78, 90, 123, 164 urea synthesis 118–20 uridine 167, 218, 258 urine testing 81 vanilloid receptors 248–9 vascular dysfunction 170 vascular endothelial growth factor (VEGF) 228 vascular endothelium 169, 172–3, 189–90 vasoconstriction 169–70 vasodilation 169–75 vegetarian diet 137–8, 141, 144–5 very long-chain fatty acids (VLCFAs) 143 viral ribonucleic acid 95 vitamin A autism spectrum disorders 261 autoimmune disease 200 fatigue 208–9 neurodegeneration 220–1 vitamin B12 autism spectrum disorders 264 autoimmune disease 201 chronic pain 249 fatigue 205, 209, 249 role in methylation cycle 98–9 see also B vitamins

vitamin C chronic pain 248 depression 258 hypertension 171–3 inter-relationship of antioxidants 183 osteoarthritis 240 ROS induced by exercise 46, 122 vitamin D autism spectrum disorders 261, 263 autoimmune disease 200 chronic pain 250 fatigue 208, 250 metabolism 115, 167 reliant on cholesterol for synthesis 185 suppressing production of autoimmune T cells 197 type 2 diabetes and insulin resistance 167 vitamin E healthy supply of ATP 43 inter-relationship of antioxidants 183 osteoarthritis 240 ROS induced by exercise 46, 122 vitamin K diet 141, 144–5 vitamin K2 244–5 Wahls’ paleo diet 144 Wahls, Terry 144 waist-to-hip ratio 152 Warburg effect 33, 75–6, 78–9, 79, 87, 234 Warburg, Otto 33, 75 water in hydroelectric dam analogy 37 importance of 31–2 recommended intake 137 shearing 122–3 Western diet 15, 70, 74, 77, 97, 125, 131, 143, 160, 265 xanthine oxidase 170, 172 zinc autism spectrum disorders 261 depression 256

327

Author Index

Abdollahi, M. 148 Abe-Higuchi, N. 255 Abedini, A. 214 Abeti, R. 244 Abramov, A.Y. 219, 244 Abreu, M.T. 233 Aburawi, S.M. 258 Abusarah, J. 138 Adams, K.F. 175 Adhami, V.M. 231 Adibhatla, R.M. 157 Adrain, C. 112, 227 Aeberli, I. 195 Aggarwal, B.B. 165, 228–9 Agostini, S. 168 Aguirre, C. 138 Aguirre, M.E.B. 90, 196 Ahmad, B. 219 Al-Dabbagh, M. 263 Albadri, M.R. 83, 132 Albert, B.B. 163, 187 Alcocer-Gómez, E. 255 Alleman, R.J. 252 Allen, A.M. 188 Alonso, E.N. 232 Altamimi, M. 258 Amadoro, G. 55 Amawi, H. 224 Amiot, M. 135 Anand, P. 222 Anderson, A.M. 229, 236, 244 Anderson, E.J. 179 Anderson, S.M. 76 Andrade, E.F. 159 Andrade, R.G. 116 Anel, A. 227 Angelova, P.R. 219 Arbid, E.J. 245 Archer, S.L. 48

328

Area-Gomez, E. 108, 212 Arendt, J.F.H. 209 Argüelles, S. 187 Armstrong, J.S. 116 Ascenzi, P. 157 Ascherio, A. 197, 200 Ashcroft, F. 160 Atamna, H. 115 Atkinson, F.S. 139 Atsmon-Raz, Y. 214 Aufschnaiter, A. 150 Auwerx, J. 126, 134 Avadhani, N.G. 125 Aviles-Olmos, I. 214 Ayala, A. 187 Azad, N. 92 Azar, S.T. 83, 132 Aziz, F. 145 Azuma, J. 167, 206 Baas, P.W. 219 Babb, S.M. 218 Bach-Faig, A. 136–7 Bading, H. 104 Bagis, S. 248 Bailey, J. 172 Bak, A.A.A. 190 Bakovic, M. 136, 140 Balogh, T. 258 Baltes, S. 209 Banerjee, S. 224, 226, 252 Bansal, Y. 251–3 Baraldi, F.G. 164 Barbour, J.A. 126 Barrett, J.S. 140–1 Bartlett, J.D. 151 Basta, G. 174 Beal, M. 219 Béaslas, O. 151

Belcaro, G. 240 Bell, R.F. 145 Bellan, M. 145 Bellanti, F. 188 Belmaker, R. 262 Beloribi-Djefaflia, S. 233, 235 Bener, A. 263 Benite-Ribeiro, S.A. 59–60 Bennett, G.G. 139 Berg, J.M. 41 Bergmans, R.S. 255 Bernatoniene, J. 182 Berod, L. 89–90, 143, 150 Berstad, A. 140 Beydoun, H.M. 83, 132 Bhakkiyalakshmi, E. 122, 167 Bhandari, P. 47 Bhatti, G.K. 150–1 Bhatti, J.S. 150–1 Bhupathiraju, S.N. 139 Bhutia, Y.D. 90 Bianco, A. 82 Biasi, F. 188 Biasutto, L. 124, 230 Biesinger, S. 171 Bikle, D.D. 167 Biondi, B. 195 Birdsall, T.C. 223 Bishop, D.J. 151 Blackstone, N. 28 Blanco, F.J. 238 Blanquer-Rossellõ, M.M. 196 Blatter, L.A. 83–4 Bliek, A.M. van der 47 Blum, D.J. 180 Bluvas, E. 132 Boden, M.J. 168 Bogeski, I. 110 Bohn, T. 122

Author I nde x

Bonaz, B. 216 Bonini, M.G. 181 Bootman, M.D. 103 Bossy-Wetzel, E. 255 Bouayed, J. 122 Bouraoui, L. 43 Bourassa, M.W. 165 Braak, H. 216 Branchi, I. 136 Branco, A.F. 81, 84 Brand, M.D. 38 Brand-Miller, J.C. 139 Breitenkamp, A.F. 261 Bridges, H.R. 55 Broadley, M.R. 102, 109 Brookes, P.S. 103 Brown, G.D. 231 Brown, M.R. 49 Bultynck, G. 106 Butow, R.A. 125 Caesar, R. 89 Cai, L. 78 Cai, N. 254 Calabrese, V. 18 Calì, T. 108, 213 Campbell, S. 254 Campisi, J. 55 Cannell, J.J. 263 Cansev, M. 218 Cantley, L.C. 87 Cantó, C. 134, 166 Cao, D. 72 Cao, Y. 155 Cardoso, S.M. 57 Carito, V. 135 Carr, A.C. 248 Carruba, M.O. 17 Carta, G. 41 Carvalho, A.F. 256 Casieri, V. 168 Cassel, S.L. 95 Castelo-Branco, C. 245 Castro-Marrero, J. 210 Caton, P.W. 71 Celsi, F. 102 Cerf, M.E. 161 Cervellati, R. 183 Chakraborty, K. 96, 208 Chakravarty, S. 256 Chander, S.J.U. 177 Chapple, I.L. 207 Chattopadhyay, M. 150 Chaudhari, N. 106 Chen, K.-H. 93 Chen, T. 51 Chesarino, N.M. 40, 91 Chevalier, S. 42 Chhabra, S. 162

Chinetti-Gbaguidi, G. 187 Cho, G. 89 Chu, C.T. 217 Chuengsamarn, S. 165 Cipolla, B.G. 145–6 Clark, A.L. 162 Clark, I.E. 217 Clark, J.B. 49 Clinton, C.M. 138 Cochemé, H.M. 38 Cohen, M.M. 183 Colin, E.M. 200 Constantin-Teodosiu, D. 63–4 Corcoran, R. 248 Correale, J. 90, 196 Cotroneo, A.M. 218 Cottin, S.C. 174 Coughlan, K.A. 55 Coussens, L.M. 224 Couturier, K. 166 Craig, C. 204 Crosby, V. 248 Crott, J.W. 257 Currie, A.R. 111 d’Adda di Fagagna, F. 55 Dagda, R.K. 217 Daily, J.W. 249 Das, L. 229 Datta, G. 137–8 Davey, G.P. 49 Davidson, M.H. 191 Dávila Guardia, J. 245 Davinelli, S. 60 De Caterina, R. 174 De Felice, F.G. 214 De La Monte, S.M. 214 de Moura, M.B. 18 de Nigris, F. 173 de Oliveira, M.R. 209, 221 De Vadder, F. 42, 165 De Vega, W.C. 205 Deb, N. 256 DeBerardinis, R.J. 226 Decuypere, J.-P. 104, 106 Dedkova, E.N. 83–4 Dedov, V.N. 249 Deitrich, R.A. 252 Del Tredici, K. 216 Delhey, L. 259, 264 D’Eliseo, D. 232 Deng, Y. 243 Dentin, R. 90 Devin, A. 121 Deyn, P.P. 220 Dhatariya, K. 82 Di Meo, S. 151 Díaz, E. 138 Diaz-Morales, N. 50

Dikalov, S.I. 140, 170–1 Dikalova, A.E. 150, 170–1 Ding, G. 243 Ding, W.X. 46 Divakaruni, A.S. 38, 107 Dixit, V.M. 155 Dixon, B. 192 Dobrian, A.D. 145 Dolan, M.F. 26–7 Dong, Y. 104 Donnelly, C. 235 Dorn, G.W. 47 dos Santos, L.S. 18 Duarte, A. 119 Dudley, S.C. 181 Duman, R.S. 258 Dungel, P. 174 Duntas, L.H. 195 Dusonchet, J. 160 Dutta, D. 167 Dutta, M. 153 Dutta, P.C. 189 Edeas, M. 155 Egnatchik, R.A. 106 El Asmar, M.S. 245 El Idrissi, A. 181 Elamin, A. 162 Elamin, M. 132 Elias, K.M. 200 Ellithorpe, R. 207 Eloi, M. 200 Emanuele, E. 253 Embley, T.M. 25 Engelborghs, S. 220 English, J. 123 Erjavec, I. 242 Esposito, K. 135 Essa, M.M. 261 Esteller, M. 229 Esteves, A.R. 57 Fabelo, N. 92 Fan, H. 229 Fan, M.J. 232 Fan, R. 201 Farez, M. 90, 196 Farooqui, A.A. 218 Farrell, G.C. 186–7 Feinman, R.D. 132 Feng, B. 182 Feniouk, B.A. 197 Feoli, A.M.P. 170 Fernandez-Marcos, P.J. 134 Ferramosca, A. 78, 135, 137, 151, 164, 186, 190, 234 Ferrari, F. 218 Ferreira, S.T. 214

329

M I TO C H O N D R I A I N H E A LT H A N D D I S E A S E

Fiorentino, M. 92 Fišar, Z. 135–6, 253 Fischer, B. 152 Fletcher, J.M. 88 Flora, G. 115 Förstermann, U. 172 Forsyth, C.B. 216 Fortin, O. 242 Foster-Powell, K. 139 Franchi, L. 95 Frank, J. 240 Frank, M. 121 Freitag, J. 196, 198 Frey, S. 85, 132 Frye, R.E. 259–61 Fujita, M. 207 Fukuda, S. 210 Galgani, J. 138 Gallagher, E.J. 223 Gallagher, J.C. 244, 262 Galløe, A.M. 175 Galluzzi, L. 52 Gálvez, R. 248 Gambuzza, M.E. 206 Ganapathy, V. 90 Gangwisch, J.E. 255 García-Corzo, L. 183 García, J.C. 104 Gareri, P. 218, 263 Garg, M. 153 Garred, P. 175 Garrido-Maraver, J. 210 Gatenby, R.A. 226 Gavriilidis, C. 150 Gazoni, F.M. 249 Geddes, J.W. 49 Georgieva, E. 224 Gerber, P.A. 187 Gerdes, H.-H. 58 Gerich, J.E. 42 Gerriets, V.A. 199 Ghanizadeh, A. 262 Ghosh, A.K. 224, 226 Ghosh, B. 18 Ghosh, S. 199 Gibson, P.R. 140–1 Gillies, R.J. 226 Giordano, S. 137–8 Giralt, A. 70, 72 Giulivi, C. 259–60 Gladwin, M.T. 171 Godos, J. 137 Goedert, M. 215 Gold, R. 150 Golde, T.E. 212 Goldring, M.B. 238 Golshani-Hebroni, S. 109 Goodpaster, B.H. 162

330

Gordon, S. 231 Gorini, A. 218 Govender, P. 126 Gozes, I. 57 Grace, P.M. 247 Graham, A. 188 Graham, D. 183 Grant, J. 210 Grant, W.B. 263 Graudal, N.A. 175 Gray, L.R. 33 Greco, E. 183 Green, K.M. 215 Greenamyre, J.T. 217 Greene, N.P. 59 Grieb, P. 208 Griffiths, K.K. 158 Grimaldi, K.A. 82 Grishko, V. 239 Grobbee, D.E. 190 Gröber, U. 181 Grosso, G. 255 Gu, Z. 232–4 Guardia-Laguarta, C. 108, 212 Guarner-Lans, V. 198 Guillaumond, F. 233, 235 Günther, T. 162 Guo, J.-M.M. 179, 187 Gupta, D. 115 Gupta, L. 83–4 Gupta, S.C. 165 Gurung, P. 96 Hadar, Y. 232 Hadgkiss, E.J. 142 Haegert, D. 197 Haegert, D.G. 197 Haghikia, A. 88–90, 150 Hah, Y.S. 201 Haim, D. 192 Hainaut, P. 223 Hajnóczky, G. 106 Hall, R. 83 Hall, W.L. 174 Hang, H.C. 91 Hardie, D.G. 54, 60 Hashim, S.A. 82 Hatch, G.M. 208 Hatcher, J.F. 157 Hatta, H. 206 Hauser, R. 238 Havouis, R. 145–6 Hawkes, C.H. 216 Haworth, R.A. 163 He, N. 243 Hecht, S.M. 116 Heiden, M.G. 87 Hellmann-Regen, J. 221 Henchcliffe, C. 219

Hendgen-Cotta, U.B. 154 Herbst, E.A.F. 262 Hernandez-Ontiveros, D.G. 221 Herrero, A. 229 Herzig, S. 261 Hill, R.L. 35 Ho, K.M. 181 Hokama, Y. 208 Hommelberg, P.P.H. 89 Hoppel, C.L. 154, 178 Hosseini, M.-J. 192–3 Hou, D.-X. 230 Houten, S.M. 39–40 Hroudová, J. 135–6, 253 Hsia, C.C.W. 26 Huang, H.C. 57, 219 Huang, S. 92 Huang, W. 250 Huang, X. 58, 177, 180 Hunter, D.J. 163 Hunter, D.R. 163 Iacobazzi, V. 77–8, 190 Icard, P. 226 Im, N.K. 243 Infantino, V. 77–8, 190, 228 Iossa, S. 151 Isaya, G. 115 Ishikado, A. 207 Ishikawa, T. 188 Israel, L. 29 Ito, T. 167, 206 Iwabu, M. 151 Iwama, H. 123 Iyer, A.K.V. 92 Jahnen-Dechent, W. 109 Jain, A. 184 Janes, K. 249 Jayakumar, T. 232 Jazwinski, S.M. 125 Jenkins, B. 40 Jeromson, S. 163 Jerosch, J. 239–40 Jha, S.K. 150–1 Jhun, J. 200 Ji, C. 110 Jiang, D. 243 Jiang, M. 229 Jiang, Y.-G. 92 Jin, L. 226 Jobin, C. 233 Johanssen, T. 104 Johnson, C. 210 Joncquel-Chevalier Curt, M. 98 Jonvik, K.L. 103 Jovaisaite, V. 126 Jump, D.B. 235

Author I nde x

Jung, S. 59, 204 Juni, R.P. 172–3 Kaats, G.R. 245 Kaddurah-Daouk, R. 98–9 Kahler, S.G. 260 Kalghatgi, S. 29 Kalogeropoulos, A.P. 175–6 Kalueff, A.V. 104 Kandler, O. 24 Kanfer, J.N. 157 Kanneganti, T.D. 96 Kanoniuk, D. 115 Kaplowitz, N. 110 Karami-Mohajeri, S. 148 Karunakaran, D. 138, 190 Kato, M. 257 Katunga, L.A. 179 Katyare, S.S. 163 Kałużna-Czaplińska, J. 157 Kaur, K. 264 Kawajiri, S. 46–8 Kazazis, C. 164 Kell, D.B. 15, 116–17 Kelm, M. 154 Kelso, G.F. 210 Kerekes, G. 150 Kern, J. 104 Kerr, J.F. 111 Ketteler, M. 109 Khan, M.A. 141 Khan, N. 231 Khattab, A. 263 Khdour, O. 116 Khoo, K.H. 229 Kietadisorn, R. 172–3 Kim, B. 173 Kim, C. 206 Kim, D.C. 162 Kim, D.Y. 84 Kim, E.K. 200 Kim, H.Y. 146, 220 Kim, J.H. 165 Kim, K. 59, 204 Kim, Y. 164 Kincaid, B. 255 Kinnally, K.W. 105 Kisters, K. 181 Kitsis, R.N. 47 Klein, P. 83–4 Ko, Y.H. 180 Koba, K. 235–6 Kobayashi, K. 241–3 Kobayashi, S. 204 Kocak, E. 155 Kone, B.C. 192, 205 Kosenko, E.A. 123 Koulman, A. 40 Kream, R.M. 254

Krebs, J. 83 Kresge, N. 35 Krols, M. 214 Ku, C. 25, 27 Kuhad, A. 251–3 Kumamoto, T. 230 Kumar, S. 255 Kusiak, A. 115 Ladurner, A. 172 Lahon, D. 256 Lai, T.W. 261 Lalia, A.Z. 207 Lampen, A. 209 Land, W.G. 203 Lane, N. 17, 27–8, 123 Lanza, I.R. 207 Lapidus, L.J. 219 Lawless, C. 52 Ledderose, C. 93–4 Lee, B.S. 151 Lee, J. 239 Lee, J.Y. 234 Lee, W.R. 188 Lema Tomé, C.M. 216 Lemasters, J.J. 53 Lenardo, M.J. 52 Leonarduzzi, G. 187–8 LeRoith, D. 223 Levy, R.J. 158 Li, F. 229 Li, H. 172 Li, J. 145 Li, N. 38, 217, 258 Li, Q. 179 Li, W. 229 Li, X. 110 Li, Y. 193 Liang, Q. 204 Lim, S. 230 Lin, S.C. 54 Lincet, H. 226 Lira, V.A. 59 Liu, C.-C. 213 Liu, C.S. 256 Liu, S. 56, 187 Liu, Z. 241 Llinàs-Arias, P. 229 Long, L. 192 Lood, C. 199 Louie, S.M. 235 Lourenço, E.V. 199 Lozovoy, M. 199 Lu, H.-K. 245 Lukens, J.R. 96 Lurie, I. 255 Mabalirajan, U. 18 MacHotka, Z. 255

MacIver, N.J. 88 MacQueen, G. 254 Maden, M. 220 Madore, C. 262–3 Maes, M. 205, 207 Mahalle, N. 153 Maheshwari, R.K. 230 Mahler, A. 201 Mahrouf-Yorgov, M. 180 Malecki, K.M. 255 Mali, A.V. 163 Manchester, M. 143 Manicassamy, S. 208 Manning, P. 65 Mantovani, M.S. 232 Manzel, A. 90 Manzo-Avalos, S. 72 Marchitti, S.A. 252 Marescau, B. 220 Margulis, L. 28 Marks, A.R. 101 Markus, M.A. 137 Maroz, A. 183 Marsden, W.N. 253 Marshall, C.B. 105 Martí Massó, J.F. 217 Martin, S.J. 112, 227 Martin, W. 17, 27–8, 123 Martinez, B. 182 Martínez-Lostao, L. 227 Martorell-Riera, A. 104 Mashima, T. 235 Masino, S.A. 83, 132 Matamoros, A.J. 219 Mathews, G.C. 83–4 Matthes, J. 261 Mauceri, D. 104 McCall, C. 248 McCarty, M.F. 252 McDaniel, S.S. 54, 60 McGlade, E. 263 McGowan, P.O. 155, 205 McIntyre, R.S. 256 Meiri, G. 262 Mejia, E.M. 208 Menendez, J.A. 43 Menzies, K.J. 255 Miao, J. 206 Michalek, R.D. 88, 199 Michan, S. 134 Mihara, M. 229 Milaneschi, Y. 256 Miller, Y. 214 Milne, J. 166 Miragoli, M. 178 Missiaen, L. 104 Miwa, K. 207 Miwa, S. 52 Mlyniec, K. 256

331

M I TO C H O N D R I A I N H E A LT H A N D D I S E A S E

Mobasheri, A. 243 Módis, K. 174 Moens, A.L. 172–3 Mohammadi-Bardbori, A. 192–3 Mohr, D.C. 198 Mollen, K.P. 216 Monaco, G. 104, 106 Montgomery, M.K. 168, 204 Moore, T.J. 139 Morán, M. 46 Morigi, M. 51 Moro, E. 136 Moro, K. 234 Mórotz, G.M. 106 Morris, B.J. 137 Morris, G. 135–6, 141, 203, 205–7 Morris, M.C. 142 Mouchiroud, L. 126 Moulinoux, J.P. 145–6 Mounier, C. 43 Mukhtar, H. 231 Mulak, A. 216 Munger, K.L. 197, 200 Muniyappa, R. 170 Muñoz, M.F. 187 Muoio, D.M. 159–60 Murakami, S. 191 Murphy, M.P. 38 Murray, A.J. 18, 82, 177, 180 Naik, E. 155 Naoum, J.J. 245 Nasirinezhad, F. 248 National Heart, Lung, and Blood Institute 140 Nätt, D. 205 Nau, H. 209 Naughton, C. 217 Ndip Agbor, V. 244 Neal, E.G. 82, 133 Neumann, W.L. 249 Newgard, C.B. 159–60 Newton, J.L. 65 Nguyen, H. 208 Ni, H.M. 46 Nicolson, G. 207 Ning, X. 232 Nisoli, E. 17 Nissilä, E. 151 Niyazov, D.M. 260 Noubiap, J.J. 244 Novak, E.A. 216 Núñez, G. 95 Ocvirk, S. 235 Oh, S. 190 Ojaimi, S. 208

332

O’Keefe, S.J. 235 Oleszycka, E. 95 Oliveira, A.M.M. 104 Olkkonen, V.M. 151 O’Neill, H.M. 54, 60 Onishi, Y. 153 Ormazabal, A. 173 Osinska, E. 115 Otero, M. 238 Packer, L. 183 Pagliai, G. 137 Pal, D. 224, 226 Pal, S. 229 Palikaras, K. 134 Pall, M.L. 209, 249 Palmer, L.J. 155, 245 Palmieri, F. 190 Palmieri, L. 259, 261 Paoli, A. 82 Papakostas, G.I. 257 Paradies, G. 263 Pardo, J. 227 Parikh, N.I. 138, 154 Park, A. 221 Park, J. 216 Park, S.-G. 89 Park, S.-H. 89 Park, S.H. 189–90 Park, Y. 164 Parry Strong, A. 83 Patchva, S. 165 Patil, P. 145 Patron, M. 101 Paul, A. 150 Payne, R.M. 68–9 Pedersen, P.L. 180 Pérez-Torres, I. 198 Perier, C. 17, 49 Perraton, L.G. 255 Persico, A.M. 259 Peuchen, S. 49 Peyrol, J. 135 Phielix, E. 161 Picca, A. 60 Pietrocola, F. 64, 67, 78 Pillay, K. 126 Pinckaers, P.J.M. 82 Pirisi, M. 145 Pitas, R.E. 213 Pivovarova, N.B. 254 Plat, J. 231 Plauth, A. 122 Plymoth, A. 223 Poddar, M.K. 252 Podszun, M. 240 Poff, A. 87 Poli, G. 188 Pollock, D.M. 169

Poplawski, M.M. 84 Poulain, L. 226 Priore, P. 135–6 Procaccini, C. 90, 195 Puig-Alcaraz, C. 264 Radi, R. 249 Ragan, M.A. 229, 236, 244 Rama, R. 104 Ramakers, J.D. 231 Rao, P.P.N. 219 Rassaf, T. 154 Rassart, E. 43 Rathmell, J.C. 88, 199 Raturi, A. 107–8 Ravi, S. 185, 187 Rayssiguier, Y. 109 Reddy, P.H. 150–1 Rego, I. 238 Resh, M.D. 91 Reyes, F.G.R. 147 Reznick, R.M. 192 Riccio, P. 77 Richardson, D.R. 114 Richter, J. 232 Rietdorf, K. 103 Ripps, H. 181 Ristow, M. 45–6, 122 Riva, C. 135 Roden, M. 161 Rodriguez, A.-M. 180 Rodriguez-Estrada, M.T. 189 Rodríguez-Rejón, A.I. 135 Rohanizadeh, R. 243 Rojo, A.I. 221 Rollins, C. 182 Rolo, A.P. 192 Rosca, M.G. 154, 178 Rosenberg, P.A. 145 Ross, D. 242 Rossano, R. 77 Rossignol, D.A. 261 Roth, T.L. 155 Rubio-Ruiz, M.E. 198 Ruderman, N.B. 54 Ruiz-Romero, C. 238 Ruscica, M. 193 Rutherford, G. 65 Saavedra-Molina, A. 72 Saffarpour, S. 248 Sagan, D. 28–9 Sagan, L. 28 Sainaghi, P.P. 145 Saint-Georges-Chaumet, Y. 155 Saleem, M. 243 Salim, S. 252 Salvemini, D. 249

Author I nde x

Sam, C.-H. 245 Samuel, J. 254 Sanders, T.A. 174 Sandoval-Acuña, C. 238 Saner, N.J. 151 Santos, J.M. 59–60 Santulli, G. 101, 178 Sato-Harada, R. 216–17 Sauvé, J.-F. 95 Savage, G.P. 189 Savage, M. 82 Schaffer, S.W. 167, 206 Schapira, A.H.V. 113 Schatz, I.J. 189 Schell, J.C. 33 Schmidt, A.M. 214 Schmidt, J. 181 Schon, E.A. 108, 212 Schwabe, R.F. 233 Schwartz, B. 232 Schwedhelm, C. 222 Schwingshackl, L. 222 Scott, B.R. 122 Seimiya, H. 235 Sen, C.K. 183 Senanayake, V.K. 143 Sendek, A. 217 Serhan, C.N. 219 Setälä, K. 29, 225 Sethi, G. 229 Shadel, G.S. 199 Shakibaei, M. 229, 243 Sharma, A. 230 Sharman, M.J. 89 Shawcross, D.L. 119 Shawgo, M. 52 Shen, Q. 46–8 Shen, W. 181 Shilovsky, G.A. 197 Shin, C.Y. 248 Shiva, S. 103 Shivappa, N. 131 Shoffner, J. 260 Shriver, L.P. 143 Shulman, G.I. 192 Shum, L.C. 241 Siddiqui, R.A. 92 Sieber, M.H. 151 Siegel, D. 242 Siervo, M. 174 Simmen, T. 107–8 Simon, C. 197, 200 Simoni, R.D. 35 Simons, K. 92 Singh, A. 239, 256 Singhal, N.K. 197, 201, 205 Sinha, A. 250 Sinha, R.A. 206, 209 Sitar, D.S. 157

Sivakumar, T. 171 Sivitz, W.I. 165 Skarlovnik, A. 192 Skarpańska-Stejnborn, A. 207 Skulachev, V.P. 197 Smith, L.M. 244, 262 Smith, R.A. 210 Sobocińska, J. 97 Sokratous, M. 197, 201 Solesio, M.E. 48–9 Song, C. 104 Sonnenschein, C. 223–4 Sorrentino, G. 157 Soto, A.M. 223–4 Soukoulis, V. 181–2, 184 Sousa, T.P.M. 192 Sowers, J.R. 170 Spain, R. 201 Spindler, M. 219 Spitzer, C. 197, 199 Spradling, A.C. 151 Sreekanth, C.N. 225 Stacpoole, P.W. 65 Staels, B. 187 Stahl, S.M. 257 Steck, S.E. 131 Stefano, G.B. 254 Stefanson, A.L. 136, 140 Steinberg, D. 139 Stewart, P.A. 261 Stolarz-Skrzypek, K. 175 Strandberg, L. 52 Strushkevich, N. 119 Stryer, L. 41 Suarez-Arroyo, I.J. 232 Subash, S. 141–2 Sui, B. 246–7 Sullivan, L.B. 226 Sullivan, P.G. 49 Sumathi, R. 171 Sun, Q. 173, 220 Supale, S. 50 Suvà, M.L. 209 Suzuki, S. 150 Svetkey, L. 139 Swank MS Foundation 144 Szabò, I. 124, 230 Szarka, A. 258 Szendroedi, J. 161 Szkudelska, K. 166 Szkudelski, T. 166 Szutowicz, A. 221 Taegtmeyer, H. 178–9 Tait, S.W.G. 95, 233 Takahashi, Y. 206 Tambini, M. 213 Tamblyn, J.A. 208 Tamizharasi, S. 171

Tamura, M. 234 Tangvarasittichai, S. 166 Tankeu, A.T. 244 Tapia, P.C. 125 Tarasov, A. 160 Tavernarakis, N. 134 Taylor, J.M.W. 188 Taylor, K.L. 196 Tengholm, A. 93, 160 Tewari, S. 59–60 Thangapazham, R.L. 230 Thomas, G. 177 Thompson, C.B. 87 Thoudam, T. 213 Tiwari, A. 115 Tiwari, S.K. 263–4 Toomre, D. 92 Toth, P.P. 187 Trenkner, E. 181 Tsukada, H. 156 Tsuruo, T. 235 Tubbs, E. 108 Turner, N. 126, 168, 204 Tuvemo, T. 162 Tymoczko, J.L. 41 Tynan, R.J. 255 Tyrlikova, I. 83–4 Ullah, F. 113 Umetani, M. 188 Ungvari, Z. 140, 170 Urtasun, M. 217 Ussher, J.R. 177, 180 Valdecantos, M.P. 71, 162 Valeur, J. 140 Valez, V. 38 Valim, M.F.C.F.A. 147 Valiyakizha Kkeveetil, C. 177 van der Bliek, A.M. 46–8 van der Giezen, M. 27 Van Houten, B. 18 Van Rooyen, D.M. 186–7 Vandenberghe, C. 83 Vanderschueren, D. 242 VanItallie, T.B. 82 Vasiliou, V. 252 Vasseur, S. 233, 235 Vaubel, R.A. 115 Vaughan, R.A. 258 Veech, R.L. 82 Velotti, F. 232 Venditti, P. 151 Venturini, M.A. 248 Vercesi, A.E. 147 Vernon, S.D. 205 Verron, E. 243 Vickers, J.C. 219

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Videla, L.A. 192 Vieira, A. 142 Vieira-Potter, V.J. 196 Vila, M. 17, 49 Villa, R.F. 218 Vinayak, M. 229 Violi, F. 193 Volman, J.J. 231 von Zglinicki, T. 52 Vos, M. 141 Wade, D.T. 201, 205 Wagner, G.R. 68–9 Walker, M.A. 94 Wallis, C. 132 Wanders, R.J.A. 39–40 Wang, H. 145 Wang, H.-L. 217 Wang, J. 182, 201 Wang, L. 258 Wang, S. 143, 195–6 Wang, X. 38, 58 Wang, Y. 240 Wang, Y.T. 261 Ward, T. 147 Weaver, D. 106 Wei, M. 134 Wei, X. 163 Wei, Y. 122 Weitkunat, K. 40 Welch, W.J. 175 Werb, Z. 224 West, A.P. 95, 199 West, J.A. 40 Wheelis, M.L. 24

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White, C.R. 137–8 White, P.J. 102, 109 Wiederkehr, A. 162 Wiener, C.D. 253 Wilcock, A. 248 Williams, J.A. 46 Williams, T.A. 25 Willis, M.S. 179 Woese, C.R. 24 Wolf, A.M. 110, 207 Wollheim, C.B. 162 Wong, K.-H. 110 Woo, J.H. 112 Woo, J.L. 55, 162 Wright, C. 92 Wu, D. 201 Wurtman, R.J. 218, 258 Wyllie, A.H. 111 Wyss, M. 98–9 Xie, G. 235 Xie, Z. 191 Xiong, X. 182 Yacoub, O. 258 Yadav, A. 195 Yalamanchili, V. 244, 262 Yan, L.-J. 135–6, 139–40, 151, 161–2, 198, 215 Yan, Z. 59 Yanagita, T. 235–6 Yang, K.C. 181 Yang, Z. 198–9 Yao, Y. 142 Yap, I.K.S. 262

Yen, P. 209 Yi, M. 106 Yilmaz, H. 245 Yin, H. 138, 150 Yoboue, E.D. 121 Yorek, M.A. 165 Youle, R.J. 47 Young, C.D. 76 Yount, J.S. 91 Yousefi, S. 245 Yu, L. 52 Yu, Z. 192, 205 Yuan, X. 233 Yubero-Serrano, E.M. 110 Yuste, J.E. 104 Zanotti, I. 189–90 Zara, V. 78, 135, 137, 151, 164, 186, 190, 234 Zhang, C.S. 54 Zhang, F. 57 Zhang, J. 16 Zhang, L. 178, 220 Zhang, M.M. 91 Zhang, P. 249 Zhang, S. 232, 261 Zhao, J. 50, 243 Zhong, H. 150 Zhou, C. 245 Zhou, G. 192 Zhou, R. 255 Zhou, S.-Y. 140 Zhu, X.-H. 18 Zoratti, M. 124, 230

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