Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 1

Part 1 book “Mitochondrial dysfunction caused by drugs and environmental toxicants” has contents: The role of transporters in drug accumulation and mitochondrial toxicity, structure–activity modeling of mitochondrial dysfunction, mitochondrial dysfunction in drug‐induced liver injury, evaluating mitotoxicity as either a single or multi‐mechanistic insult in the context of hepatotoxicity,…. and other contents.

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Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

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Mitochondrial Dysfunction Caused by Drugs

and Environmental Toxicants

Volume I

Edited by

Yvonne Will, PhD, ATS Fellow

Pfizer Drug Safety R&D, Groton, CT, USA

James A Dykens

Eyecyte Therapeutics

Califormia, USA

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This edition first published 2018

All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Yvonne Will and James A Dykens to be identified as the editors of this work has been asserted in accordance with law.

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Library of Congress Cataloging‐in‐Publication Data

Names: Will, Yvonne, editor | Dykens, James Alan, 1951– editor.

Title: Mitochondrial dysfunction caused by drugs and environmental toxicants /

edited by Yvonne Will, James A Dykens.

Description: Hoboken, NJ : John Wiley & Sons, 2018 | Includes bibliographical references and index |

Identifiers: LCCN 2017046043 (print) | LCCN 2017048850 (ebook) | ISBN 9781119329732 (pdf) |

ISBN 9781119329749 (epub) | ISBN 9781119329701 (cloth)

Subjects: LCSH: Drugs–Toxicology | Mitochondrial pathology.

Classification: LCC RA1238 (ebook) | LCC RA1238 M58 2018 (print) | DDC 615.9/02–dc23

LC record available at https://lccn.loc.gov/2017046043

Cover Design: Wiley

Cover Image: Courtesy of Sylvain Loric

Set in 10/12pt Warnock by SPi Global, Pondicherry, India

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

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Contents

List of Contributors xvii

Foreword xxix

Part 1 Basic Concepts 1

1 Contributions of Plasma Protein Binding and Membrane Transporters to Drug‐Induced

Mitochondrial Toxicity 3

Gavin P McStay

1.1 Drug Accumulation 3

1.2 Small Molecule Delivery to Tissues 4

1.3 Entry into Cells 7

1.4 Transport Out of Cells 8

1.5 Entry into Mitochondria 10

1.6 Export from Mitochondria 11

1.7 Concluding Remarks 11

References 11

2 The Role of Transporters in Drug Accumulation and Mitochondrial Toxicity 15

Kathleen M Giacomini and Huan‐Chieh Chien

2.1 Introduction to Chapter 15

2.2 The Solute Carrier (SLC) Superfamily 15

2.3 Transporters as Determinants of Drug Levels in Tissues and Subcellular Compartments 17

2.4 Drug Transporters in the Intestine 18

2.5 Drug Transporters in the Liver 18

2.6 Drug Transporters in the Kidney 19

3 Structure–Activity Modeling of Mitochondrial Dysfunction 25

Steve Enoch, Claire Mellor, and Mark Nelms

3.1 Introduction 25

3.1.1 Mitochondrial Structure and Function 26

3.1.2 Mechanisms of Mitochondrial Toxicity 26

3.2 Mitochondrial Toxicity Data Sources 26

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vi

3.4 Mechanistic Chemistry Covered by the Existing Structural Alerts 31

3.5 Structural Alert Applicability Domains: Physicochemical Properties 33

3.6 Future Direction: Structure–Activity Studies for Other Mechanisms of Mitochondrial Toxicity 33

4.3 Targeting and Significance of Multiple Forms of Mitochondrial CYPs 36

4.3.1 Mitochondrial Import of CYP1A1 38

4.3.2 Mitochondrial Import of CYP1B1 39

4.3.3 Mitochondrial Import of CYP2C8 39

4.3.4 Mitochondrial Import of CYP2D6 39

4.3.5 Mitochondrial Import of CYP2B1 and CYP2E1 40

4.3.6 Import Mechanism of GSH‐Conjugating GSTA4‐4 40

4.4 Variations in Mitochondrial CYPs and Drug Metabolism 40

4.5 Physiological and Toxicological Significance of Mitochondria‐Targeted CYPs 41

4.6 Mitochondrial CYPs and Cell Signaling 42

4.7 Conclusion 42

Acknowledgment 43

References 43

Part 2 Organ Drug Toxicity: Mitochondrial Etiology 47

5 Mitochondrial Dysfunction in Drug‐Induced Liver Injury 49

Annie Borgne‐Sanchez and Bernard Fromenty

5.2 Structure and Physiological Role of Mitochondria 49

5.2.1 Structure and Main Components of Mitochondria 49

5.2.2 Oxidation of Pyruvate and Fatty Acids 50

5.2.3 Production of ATP 50

5.2.4 Production of ROS as Signaling Molecules 51

5.3 Main Consequences of Hepatic Mitochondrial Dysfunction 51

5.3.1 Consequences of Mitochondrial β‐Oxidation Inhibition 51

5.3.2 Consequences of MRC Inhibition 52

5.3.3 Consequences of Mitochondrial Membrane Permeabilization 52

5.4 Main Hepatotoxic Drugs Inducing Mitochondrial Dysfunction 53

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Contents vii

6 Evaluating Mitotoxicity as Either a Single or Multi‐Mechanistic Insult in the Context of Hepatotoxicity 73

Amy L Ball, Laleh Kamalian, Carol E Jolly, and Amy E Chadwick

6.2 Important Considerations When Studying Drug‐Induced Mitochondrial Toxicity in the Liver 74

6.2.1 Xenobiotic Metabolism 74

6.2.2 Biliary System 75

6.2.2.1 Mechanisms of Bile Acid and Bile Salt‐Mediated Mitochondrial Toxicity 76

6.2.2.2 Bile Acid Accumulation Following Mitochondrial Perturbation 76

6.2.2.3 Bile Acid Toxicity Resulting from Dual Inhibition of Mitochondrial Function and Bile Salt Export 76

6.4.1 Acetaminophen: Multi‐Mechanistic Mitochondrial Hepatotoxicity 82

6.4.2 Flutamide: Multi‐Mechanistic Mitochondrial Hepatotoxicity 85

6.4.3 Fialuridine: A Case of Chronic, Direct Mitochondrial Toxicity 86

References 87

7 Cardiotoxicity of Drugs: Role of Mitochondria 93

Zoltan V Varga and Pal Pacher

7.1.1 Mitochondrial Energy Homeostasis in Cardiomyocytes 93

7.1.2 Mitochondrial Oxidative Stress in Cardiomyocytes 94

7.1.2.1 Sources of Mitochondrial Reactive Oxygen Species 95

7.1.2.2 Mitochondrial Antioxidant Defense 96

7.1.3 Birth and Death of Cardiac Mitochondria 96

7.1.3.1 Mitochondrial Biogenesis 96

7.1.3.2 Mitophagy and Mitochondrial Apoptosis 97

7.2 Cardiotoxic Drugs That Cause Mitochondrial Dysfunction 97

7.2.1 Cardiotoxicity During Cancer Chemotherapy 97

7.2.1.6 Imatinib Mesylate‐Induced Cardiotoxicity 100

7.2.1.7 Cardiotoxicity of Antiangiogenic Drugs 100

7.2.2 Cardiotoxicity of Antiviral Drugs 100

7.2.3 Cardiotoxicity of Addictive Drugs 101

7.2.3.1 Cardiotoxicity in Chronic Alcohol Use Disorder 101

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viii

7.2.3.2 Cardiotoxicity in Cocaine Abuse 101

7.2.3.3 Cardiotoxicity in Methamphetamine and Ecstasy Abuse 102

7.2.3.4 Cardiotoxicity of Synthetic Cannabinoids 102

7.3 Conclusions 102

References 102

8 Skeletal Muscle Mitochondrial Toxicity 111

Eric K Herbert, Saul R Herbert, and Karl E Herbert

8.2.2.2 Evidence for Direct Effects of Statins on Mitochondrial Function 116

8.3 AZT and Mitochondrial Myopathy 120

8.4 Do Other Nucleoside Analogue Drugs Cause Myopathy? 123

8.5 Other Drugs Possibly Associated with Myopathy Due to Mitochondrial Toxicity 123

References 124

9 Manifestations of Drug Toxicity on Mitochondria in the Nervous System 133

Jochen H M Prehn and Irene Llorente‐Folch

9.1 Introduction: Mitochondria in the Nervous System 133

9.2 Mitochondrial Mechanisms of Peripheral Neuropathy 135

9.2.1 Reverse Transcriptase Inhibitors 136

9.2.2 Chemotherapy‐Induced Peripheral Neuropathies (CIPN) 136

9.2.2.1 Microtubule‐Modifying Agents and Mitochondria: Paclitaxel and Vincristine 137 9.2.2.2 Platinum Compounds and Mitochondria: Oxaliplatin 138

9.2.2.3 Protease Inhibitor Bortezomib and Mitochondria 138

9.4.2 Mitochondrial Disorders, Hearing Loss, and Ototoxicity 145

9.5 Mitochondrial Mechanisms of Central Nervous System injury 146

9.5.1 Mitochondrial Mechanisms of Neuronal Injury 146

9.5.2 Potential Manifestations of Drug‐Induced Mitochondrial Dysfunction in the CNS 149

9.6 Conclusion 149

References 150

10 Nephrotoxicity: Increasing Evidence for a Key Role of Mitochondrial Injury

and Dysfunction and Therapeutic Implications 169

Ana Belén Sanz, Maria Dolores Sanchez‐Niño, Adrian M Ramos, and Alberto Ortiz

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Contents ix

10.3.4 Calcium Detoxification by Mitochondria: Role of Mitochondrial Permeability Transition Pore (MPT) 171

10.4 Evidence of Mitochondrial Injury in Nephrotoxicity 171

10.4.1 Morphological Changes 171

10.4.2 Mitochondrial Dysfunction 172

10.4.3 Mitochondrial Gene Expression 172

10.5 Calcineurin Inhibitor Nephrotoxicity 172

10.5.1 Calcineurin Inhibitors: Mitochondrial Dysfunction 172

10.5.2 Apoptosis in CsA Nephrotoxicity 173

10.6 HAART and Nephrotoxicity 175

10.6.1 The Transporters 176

10.6.2 HAART and Mitochondrial Dysfunction 177

10.6.3 Nucleotide Antiviral Drugs and Tubular Cell Apoptosis 177

10.7 Other Nephrotoxic Drugs and Mitochondria 177

10.7.1 Anticancer Drugs: Cisplatin 177

10.7.2 Antibiotics: Aminoglycosides and Polymyxins 178

10.7.3 Iron Chelators: Deferasirox 178

10.7.4 Environmental Nephrotoxins: Aristolochic Acid 178

10.7.5 Endogenous Nephrotoxins: Glucose, Glucose Degradation Products, and Heme 178

10.8 Therapeutic Implications and Future Lines of Research 178

Acknowledgments 179

References 179

11 Mammalian Sperm Mitochondrial Function as Affected by Environmental Toxicants,

Substances of Abuse, and Other Chemical Compounds 185

Sandra Amaral, Renata S Tavares, Sara Escada‐Rebelo, Andreia F Silva, and João Ramalho‐Santos

11.6.5 Lycopene and Fatty Acids 193

11.7 Natural Plant Products 193

12 Biological and Computational Techniques to Identify Mitochondrial Toxicants 207

Robert B Cameron, Craig C Beeson, and Rick G Schnellmann

12.1 Identifying Mitochondrial Toxicants 207

12.2 Models to Identify Mitochondrial Toxicants 208

12.3 Computational Models for the Identification and Development of Mitochondrial Toxicants 210

References 212

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x

13 The Parallel Testing of Isolated Rat Liver and Kidney Mitochondria Reveals a Calcium‐Dependent Sensitivity

to Diclofenac and Ibuprofen 217

Sabine Schulz, Sabine Borchard, Tamara Rieder, Carola Eberhagen, Bastian Popper, Josef Lichtmannegger,

Sabine Schmitt, and Hans Zischka

13.2 Methods 218

13.2.1 Parallel Isolation of Mitochondria from Rat Tissues 218

13.2.2 Electron Microscopy 220

13.2.3 Assessment of the Mitochondrial Membrane Potential (MMP) 220

13.2.4 Analyses of the Mitochondrial Permeability Transition (MPT) 220

13.2.5 Miscellaneous 220

13.3 Results and Discussion 220

13.3.1 Parallel Isolation of Intact Mitochondria from Various Rat Tissues 220

13.3.2 Ibuprofen and Diclofenac Differently Impair the MMP of Mitochondria from Rat Liver and Kidney 221 13.3.3 Ibuprofen and Diclofenac Toxicity on Isolated Mitochondria Is Markedly Increased by Calcium 223

13.3.4 Cyclosporine A (CysA) Provides Mitochondrial Protection to Ibuprofen/Ca2+‐Induced Damage 223

References 226

Rui F Simões, Teresa Cunha‐Oliveira, Cláudio F Costa, Vilma A Sardão, and Paulo J Oliveira

14.1 Mitochondria as a Biosensor to Measure Drug‐Induced Toxicities: Is It Relevant? 229

14.2 Drug‐Induced Cellular Bioenergetic Changes: What Does It Mean and How Can We Measure It? 230 14.2.1 Pinpointing Mitochondrial Toxicity: Manipulation of Culture Media Fuels 230

14.2.2 Oxygen Consumption 231

14.2.3 ATP, ADP, and AMP Measurements 233

14.2.4 Respiratory Chain and ATP Synthase Enzymatic Activities 234

14.3 Evaluation of Mitochondrial Physiology 235

14.3.1 Measuring Reactive Oxygen Species (ROS) Production with Oxidant-sensitive Probes 235

14.3.2 Monitoring Mitochondrial Transmembrane Electric Potential 236

14.3.3 Calcium Flux Measurements 238

14.3.4 Measuring the Activity of the Mitochondrial Permeability Transition Pore (MPTP) 239

References 241

15 Combined Automated Measurement of Respiratory Chain Complexes and Oxidative Stress: A First Step

to an Integrated View of Cell Bioenergetics 249

Marc Conti, Thierry Delvienne, and Sylvain Loric

15.2 Technology 250

15.2.1 OXPHOS Complex Measurements 252

15.2.2 OS Pathway Measurements 252

15.3 Applications of Functional OXPHOS and OS Measurements in Drug Evaluation 253

15.3.1 Combined OXPHOS and OS Measurements in Drug Toxicity Evaluation 253

15.3.2 Glucose as an Underestimated OXPHOS and OS Metabolic Modifier in Cultured Cells 255

15.4 Versatility of the Technology 259

15.5 Conclusions and Future Perspectives 261

References 261

16 Measurement of Mitochondrial Toxicity by Flow Cytometry 265

Padma Kumar Narayanan and Nianyu Li

16.2 Evaluation of Mitochondrial Function by Flow Cytometry 265

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16.2.1 Mitochondrial Membrane Potential (MMP) Measurement 265

16.2.2 Mitochondrial Reactive Oxygen Species (ROS) Measurement 268

16.3 Evaluation of Xenobiotics‐Induced Mitochondrial Toxicity by Flow Cytometry 268

16.3.1 Cell Culture Conditions: Glucose‐ versus Galactose‐Containing Media 268

16.3.2 Loading Fluorescent Probes 269

17 MitoChip: A Transcriptomics Tool for Elucidation of Mechanisms of Mitochondrial Toxicity 275

Varsha G Desai, and G Ronald Jenkins

17.1 Development of Mitochondria‐Specific Gene Expression Array (MitoChip) 275

17.2 Mouse MitoChip: Assessment of Altered Mitochondrial Function in Mouse Models 277

17.2.1 Flutamide‐Induced Liver Toxicity in Sod2+/− Mice 277

17.2.2 Cisplatin‐Induced Acute Kidney Toxicity in KAP2‐PPARα Transgenic Mice 279

17.2.3 Doxorubicin‐Induced Cardiotoxicity in B6C3F1 Mice 283

17.3 Rat MitoChip: Assessment of Altered Mitochondrial Function in a Rat Model 286

17.3.1 Doxorubicin‐Induced Cardiotoxicity in SHR/SST‐2 Rat Model 287

18 Using 3D Microtissues for Identifying Mitochondrial Liabilities 295

Simon Messner, Olivier Frey, Katrin Rössger, Andy Neilson, and Jens M Kelm

18.1 Significance of Metabolic Profiling in Drug Development: Current Tools

and New Technologies 295

18.2 Use of 3D Microtissues to Detect Mitochondrial Liabilities 296

18.2.1 Limitations of Currently Used In Vitro Cell Models 296

18.2.2 General Characteristics of 3D Microtissues 296

18.2.3 3D Microtissue‐Based Assessment of Mitochondrial Activity 297

18.2.4 Difference of Spare Respiratory Capacity in 2D versus 3D Cultures 297

18.3 SRC‐Based Detection of Mitochondrial Liabilities in 3D Human Liver Microtissues 299

18.4 SRC‐Based Detection of Mitochondrial Liabilities in Human Cardiac Microtissues 301

19.6 Hepatotoxicity with Mitochondrial Dysfunction 307

19.7 Hyperactivity of the Mitochondrial Stress Response in Mice 308

19.8 Summary 309

References 309

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xii

20 Measurement of Oxygen Metabolism In Vivo 315

M P J van Diemen, R Ubbink, F M Münker, E G Mik, and G J Groeneveld

20.1 Introduction: The Importance of Measuring Mitochondrial Function in Drug Trials 315

20.2 Methods: In Vivo Methods to Measure Drug Effects on Mitochondrial Function in a Clinical Setting 316

20.3 Measuring Mitochondrial Oxygen Consumption with the Protoporphyrin IX–Triplet

State Lifetime Technique 317

20.4 Features of a Novel COMET Measurement System: The First Bedside Monitor of

Cellular Oxygen Metabolism 317

20.5 Clinical Trial: Effect of Simvastatin on Mitochondrial Function In Vivo in Healthy Volunteers 317

References 319

21 Detection of Mitochondrial Toxicity Using Zebrafish 323

Sherine S L Chan and Tucker Williamson

21.4.2 Reactive Oxygen Species 335

21.4.3 Mitochondrial Dynamics and Mitochondrial Membrane Potential 335

21.4.4 Mitochondrial DNA Stability 337

21.5 Conclusions and Future Directions 338

References 338

22 MiRNA as Biomarkers of Mitochondrial Toxicity 347

Terry R Van Vleet and Prathap Kumar Mahalingaiah

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23.2 Acetaminophen Overdose as a Model for Biomarker Discovery 373

23.3 Acetaminophen Overdose: Mechanisms of Toxicity in

Mice and Man 374

23.3.1 Drug Metabolism and Protein Adducts 374

23.3.2 Critical Role of Mitochondria in APAP Hepatotoxicity 374

23.4 Biomarkers of Mitochondrial Injury 375

23.4.1 Glutamate Dehydrogenase 375

23.4.2 Mitochondrial DNA (mtDNA) 376

23.4.3 Nuclear DNA 377

23.4.4 Acylcarnitines 378

23.4.5 Carbamoyl Phosphate Synthetase 378

23.4.6 Ornithine Carbamyl Transferase (OCT) 378

References 379

24 Acylcarnitines as Translational Biomarkers of Mitochondrial Dysfunction 383

Richard D Beger, Sudeepa Bhattacharyya, Pritmohinder S Gill, and Laura P James

25 Mitochondrial DNA as a Potential Translational Biomarker of Mitochondrial Dysfunction

in Drug‐Induced Toxicity Studies 395

Afshan N Malik

25.2 The Mitochondrial Genome 396

25.3 Is Mitochondrial DNA a Useful Biomarker of Mitochondrial Dysfunction 397

25.4 Methodological Issues for Measuring Mitochondrial DNA Content 399

25.5 Acquired Mitochondrial DNA Changes in Human Diseases 401

25.6 Conclusions and Future Directions 402

References 403

26 Predicting Off‐Target Effects of Therapeutic Antiviral Ribonucleosides: Inhibition

of Mitochondrial RNA Transcription 407

Jamie J Arnold and Craig E Cameron

26.2 Therapeutic Ribonucleoside Inhibitors Target RNA Virus Infections 407

26.3 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Mediate Mitochondrial Toxicity 408

26.4 Mitochondrial Dysfunction Is an Unintended Consequence of Clinical Drug Candidates 409

26.5 Mitochondrial Transcription as an “Off‐Target” of Antiviral Ribonucleosides 410

26.6 Evaluation of Substrate Utilization by POLRMT In Vitro 410

26.6.1 Determination of the Efficiency of Incorporation by POLRMT 412

26.6.2 Determination of the Sensitivity to Inhibition: Mitovir Score 413

26.7 Direct Evaluation of Mitochondrial RNA Transcripts in Cells 414

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27 Imaging of Mitochondrial Toxicity in the Kidney 419

Andrew M Hall, Joana R Martins, and Claus D Schuh

27.1 Mitochondria in the Kidney 419

27.2 Drug Toxicity in the Kidney 421

27.3 Fluorescence Microscopy 421

27.3.1 Multiphoton Microscopy 421

27.4 Assessment of Mitochondrial Function with Fluorescence Microscopy 422

27.4.1 Mitochondrial Membrane Potential and pH 422

27.4.2 Mitochondrial Redox State 422

27.4.3 Mitochondrial Reactive Oxygen Species Production 422

27.5 Ex Vivo Imaging of Mitochondria in the Kidney 423

27.5.1 Live Imaging of Kidney Slices 423

27.6 Intravital Imaging of Mitochondria in the Kidney 423

27.7 Recent Technical Developments in Intravital Kidney Imaging 424

28 Imaging Mitochondrial Membrane Potential and Inner Membrane Permeability 429

Anna‐Liisa Nieminen, Venkat K Ramshesh, and John J Lemasters

28.2 Isolated Mitochondria 429

28.2.1 Nernstian Distribution of Fluorescent Probes 431

28.2.2 Monitoring Membrane Potential in Isolated Mitochondria 431

28.2.3 Pitfalls with Potential‐Indicating Fluorophores 431

28.3 Imaging of Membrane Potentials in Single Intact Cells 433

28.3.1 Image Acquisition and Processing 433

28.3.2 Background Subtraction 434

28.3.3 Fluorescence of the Extracellular Space 434

28.3.4 Pixel‐by‐Pixel Calculation of Ψ 434

28.4 Mitochondrial Permeability Transition 435

28.4.1 Swelling Assay of the MPT 436

28.4.2 Release of Carboxydichlorofluorescein 437

28.4.3 Visualizing the MPT in Intact Cells 437

28.4.4 Plasma Membrane Permeability 438

29.1 MRS Methods in Skeletal Muscle 443

29.2 The Metabolic and Physiological Background to 31P MRS Studies of Muscle 444

29.3 Physiological Principles in the Quantitative Analysis of Dynamic 31P MRS Data 444

29.4 Approaches to Measuring Mitochondrial Function In Vivo 446

29.5 Some Practical and Experimental Considerations in 31P MRS Studies of Muscle 446

29.6 31P MRS Studies in Resting Muscle 447

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29.7 31P MRS Magnetization Transfer Methods 448

29.8 Muscle Exercise Responses Studied by 31P MRS 448

29.9 Mitochondrial Function Studied by 31P MRS in Recovery from Exercise 449

29.10 Validating MRS‐Based Measures of Mitochondrial Function 450

29.11 Conclusions and Summary 451

References 452

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List of Contributors

Sandra Amaral

Biology of Reproduction and Stem Cell Group,

CNC—Center for Neuroscience and Cell Biology

Department of Molecular and Cellular Pharmacology,

MRC Centre for Drug Safety Science,

The Institute of Translational Medicine

The University of Liverpool

Daniel José Barbosa

Cell Division Mechanisms GroupInstituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto

PortoPortugal

Maria de Lourdes Bastos

UCIBIO, REQUIMTE (Rede de Química e Tecnologia),

Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia

Universidade do PortoPorto

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Section of Clinical Pharmacology and Toxicology

Arkansas Children’s Hospital

Institute of Molecular Toxicology and Pharmacology,

Helmholtz Center Munich

German Research Center for Environmental Health

Department of Drug Discovery and Biomedical

Sciences, College of Graduate Studies

Medical University of South Carolina

Charleston, SC

USA

João Paulo Capela

Universidade do Portoand

FP‑ENAS (Unidade de Investigação UFP em Energia, Ambiente e Saúde), CEBIMED (Centro de Estudos em Biomedicina), Faculdade de Ciências da Saúde

Universidade Fernando PessoaPorto

Portugal

Francesc Cardellach

Muscle Research and Mitochondrial Function Laboratory, Cellex‐IDIBAPS, Faculty of Medicine and Health Science‐University of Barcelona, Internal Medicine Department‐Hospital Clínic

of Barcelona (HCB)Barcelona

andCIBERERMadridSpain

Félix Carvalho

Marc Catalán-García

Muscle Research and Mitochondrial Function Laboratory, Cellex‐IDIBAPS, Faculty of Medicine and Health Science‐University of Barcelona, Internal Medicine Department‐Hospital Clínic of Barcelona (HCB)

BarcelonaandCIBERERMadridSpain

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List of Contributors xix

Amy E Chadwick

Ana Raquel Coelho

CNC—Center for Neuroscience and Cell

Biology, University of Coimbra, UC Biotech,

IMRB U955EQ7, Mondor University Hospitals;

Créteil & URDIA, Saints Pères Faculty of Medicine

Jason Czachor

Wayne State University School of MedicineChildren’s Hospital of Michigan

Detroit, MIUSA

Thierry Delvienne

MetabiolabBrusselsBelgium

Varsha G Desai

Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological ResearchU.S Food and Drug Administration

Jefferson, ARUSA

David A Dunn

Department of Biological SciencesState University of New York at OswegoOswego, NY

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List of Contributors

xx

Sara Escada‐Rebelo

CNC—Center for Neuroscience and Cell Biology,

University of Coimbra, UC Biotech,

Malalties infeccioses i resposta inflamatòria

sistèmica en pediatria, Unitat d’Infeccions, Servei

INSERM, INRA, Université Rennes, UBL, Nutrition

Metabolisms and Cancer (NuMeCan)

Rennes

France

Jeffrey L Galinkin

Department of AnesthesiaUniversity of Colorado School of Medicineand

CPC Clinical ResearchAurora, CO

USA

Priya Gandhi

Department of BiologyCollege of Science Northeastern UniversityBoston, MA

USA

Laura García-Otero

BCNatal—Barcelona Center for Maternal‐Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), IDIBAPS, University of Barcelona

Glòria Garrabou

Muscle Research and Mitochondrial Function Laboratory, Cellex‐IDIBAPS, Faculty of Medicine and Health Sciences‐University of Barcelona, Internal Medicine Department‐Hospital Clínic of Barcelona (HCB)

Mariana Gerschenson

John A Burns School of MedicineUniversity of Hawaii at ManoaHonolulu, HI

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List of Contributors xxi

Little Rock, AR

USA

Young‐Mi Go

Department of Medicine, Division of Pulmonary,

Allergy and Critical Care Medicine

Emory University

Atlanta, GA

USA

Ingrid González‐Casacuberta

Muscle Research and Mitochondrial Function

Laboratory, Cellex‐IDIBAPS, Faculty of Medicine

and Health Science‐University of Barcelona,

Internal Medicine Department‐Hospital Clínic of

Josep Maria Grau

Laboratory, Cellex‐IDIBAPS, Faculty of

Medicine and Health Science‐University of Barcelona,

Internal Medicine Department‐Hospital Clínic of

USA

Mariona Guitart‐Mampel

Muscle Research and Mitochondrial Function Laboratory, Cellex‐IDIBAPS, Faculty of Medicine and Health Sciences‐University of Barcelona, Internal Medicine Department‐Hospital Clínic of Barcelona (HCB)

Andrew M Hall

Institute of Anatomy, University of Zurichand

Department of NephrologyUniversity Hospital ZurichZurich

LiverpoolUK

Eric K Herbert

University of NottinghamNottingham

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Ana Sandra Hernández

BCNatal—Barcelona Center for Maternal‐Fetal and

Neonatal Medicine (Hospital Clínic and Hospital Sant

Joan de Deu), IDIBAPS, University of Barcelona

Division of Cardiology, Department of Medicine

University of Colorado Anschutz Medical

Campus School of Medicine

Aurora, CO

USA

Ashley Hill

Wayne State University School of Medicine

Children’s Hospital of Michigan

Dean P Jones

Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine

Emory Universityand

HERCULES Exposome Research Center, Department of Environmental HealthRollins School of Public HealthAtlanta, GA

USA

Diana Luz Juárez-Flores

Jens M Kelm

InSphero AGSchlierenSwitzerland

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List of Contributors xxiii

Department of Endocrinology and Nutrition

Amiens University Hospital

Amiens

France

Hong Kyu Lee

Department of Internal Medicine

College of Medicine, Eulji University

Seoul

South Korea

John J Lemasters

Center for Cell Death, Injury & Regeneration,

Medical University of South Carolina;

Department of Drug Discovery & Biomedical Sciences

Department of Biochemistry & Molecular Biology

Charleston, SC

USA

and

Institute of Theoretical and Experimental Biophysics,

Russian Academy of Sciences

Irene Llorente‐Folch

Department of Physiology and Medical Physics Royal College of Surgeons in Ireland

123 St Stephen’s GreenDublin 2

Ireland

Sylvain Loric

IMRB U955EQ7, Mondor University Hospitals;

Créteil & URDIA, Saints Pères Faculty of MedicineDescartes University

ParisFrance

Anthony L Luz

Nicholas School of the EnvironmentDuke University

Durham, NCUSA

Prathap Kumar Mahalingaiah

Department of Investigative Toxicology and Pathology, Preclinical Safety Division

AbbVieNorth Chicago, ILUSA

Afshan N Malik

Diabetes Research Group, School of Life Course Sciences, Faculty of Life Sciences and MedicineKing’s College London

LondonUK

Trang 22

xxiv

Gavin P McStay

Department of Life Sciences

New York Institute of Technology

Old Westbury, NY

USA

Claire Mellor

School of Pharmacy and Biomolecular Sciences

Liverpool John Moores University

Jose César Milisenda

Laboratory, Cellex‐IDIBAPS, Faculty of Medicine and

Health Science‐University of Barcelona, Internal

Medicine Department‐Hospital Clínic of

F M Münker

Photonics Healthcare B.V

UtrechtThe Netherlands

Padma Kumar Narayanan

Ionis PharmaceuticalsCarlsbad, CA

USA

Viruna Neergheen

Neurometabolic UnitNational HospitalLondon

UK

Andy Neilson

Agilent TechnologiesSanta Clara, CAUSA

Mark Nelms

School of Pharmacy and Biomolecular SciencesLiverpool John Moores University

LiverpoolUKandUS‐EPARaleigh‐Durham, NCUSA

Trang 23

List of Contributors xxv

Anna‐Liisa Nieminen

Center for Cell Death, Injury & Regeneration,

Departments of Drug Discovery & Biomedical Sciences

Charleston, SC

USA

and

Institute of Theoretical

and Experimental Biophysics,

Russian Academy of Sciences

Pushchino

Russian Federation

Antoni Noguera‐Julian

Malalties infeccioses i resposta inflamatòria

sistèmica en pediatria, Unitat d’Infeccions,

UOC Neurologia, Fondazione IRCCS Ca’

Granda – Ospedale Maggiore PoliclinicoMilan

Italy

Carl A Pinkert

Department of Biological Sciences, College of Arts and SciencesThe University of AlabamaTuscaloosa, AL

Trang 24

xxvi

João Ramalho‐Santos

Center for Cell Death, Injury & Regeneration, Medical

University of South Carolina;

Departments of Drug Discovery & Biomedical Sciences

On Sabbatical from Department of Biochemistry

College of Medicine and Health Sciences, United Arab

Emirates University

Al Ain

UAE

Hiedy Razoky

Detroit, MI

USA

Tamara Rieder

Institute of Toxicology and Environmental Hygiene

Technical University Munich

UOC Neurologia, Fondazione IRCCS Ca’

Granda – Ospedale Maggiore PoliclinicoMilan

Italy

Katrin Rössger

InSphero AGSchlierenSwitzerland

Boston Children’s HospitalBoston, MA

USA

Maria Dolores Sanchez‐Niño

Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz

Universidad Autónoma de MadridMadrid

Spain

Alessandro Santini

Dipartimento di Anestesia, Rianimazione ed Emergenza‐Urgenza, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico

Milan, Italy

Trang 25

List of Contributors xxvii

Ana Belén Sanz

Instituto de Investigación Sanitaria de la Fundación

Institute of Toxicology and Environmental Hygiene

Technical University Munich

Neuherberg

Germany

Andreia F Silva

Kosta Steliou

Boston University School of Medicine, Cancer Research Center

Boston, MAand

PhenoMatriX, Inc

Natick, MAUSA

Renata S Tavares

Biology of Reproduction and Stem Cell Group, CNC—Center for Neuroscience and Cell BiologyUniversity of Coimbra

CoimbraPortugal

Jonathan L Tilly

Department of BiologyCollege of Science, Northeastern UniversityBoston, MA

USA

R Ubbink

Department of AnesthesiologyErasmus MC

RotterdamandPhotonics Healthcare B.V

UtrechtThe Netherlands

Karan Uppal

Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine

Emory UniversityAtlanta, GAUSA

M P J van Diemen

Centre for Human Drug ResearchLeiden

The Netherlands

Trang 26

xxviii

Terry R Van Vleet

Department of Investigative Toxicology and Pathology,

Preclinical Safety Division

AbbVie

North Chicago, IL

USA

Zoltan V Varga

Laboratory of Cardiovascular Physiology

and Tissue Injury

National Institutes of Health/NIAAA

Bethesda, MD

USA

Eneritz Velasco‐Arnaiz

Malalties infeccioses i resposta inflamatòria sistèmica

en pediatria, Unitat d’Infeccions, Servei de Pediatria

Institut de Recerca Pediàtrica Hospital Sant Joan de Déu

Barcelona

Spain

Luke Wainwright

Department of Molecular Neuroscience

Institute of Neurology, University College of London

London

UK

Douglas I Walker

Department of Medicine, Division of Pulmonary,

Allergy and Critical Care Medicine

Cecilia C Low Wang

Division of Endocrinology, Metabolism and Diabetes,

USA

Benjamin L Woolbright

Department of Pharmacology, Toxicology &

TherapeuticsUniversity of Kansas Medical CenterKansas City, KS

MunichGermany

Marjan Aghvami

Department of Toxicology and Pharmacology Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences Tehran, Iran

Mohammad Hadi Zarei,

Parvaneh Naserzadeh

Trang 27

The field of mitochondrial medicine is enjoying a renais‑

sance driven largely by advances in molecular biology

and genetics The first draft sequence of the human

mitochondrial genome in 1981 provided the critical

blueprint that enabled the identification of the first point

and single large‐scale deletion mutations of mitochon‑

drial DNA (mtDNA) in 1988 To date, more than 270 dis‑

tinct mtDNA point mutations and hundreds of mtDNA

deletions have been identified Subsequent sequencing

of the human nuclear genome in the early 2000s helped

to catalyze the discovery of approximately 1000 nuclear

genes that, together with the mtDNA, encode the mito‑

chondrial proteome With a complete parts list, it has

been possible to delve deep into the molecular basis of

Mendelian mitochondrial disorders, with more than 200

nuclear disease genes now identified There is now

widespread consensus that mitochondrial dysfunction

contributes to a spectrum of human conditions, ranging

from rare syndromes to common degenerative diseases

to the aging process itself

Today, there is great excitement that in the coming dec‑

ade, new medicines will become available that alleviate

disease by targeting mitochondria At the same time, there is

widespread appreciation that many drugs fail clinical trials

because of their mitochondrial liabilities Mitochondrial

Dysfunction Caused by Drugs and Environmental Toxicants

represents one of the most important textbooks for

those hoping to target mitochondria, as well as for those

wanting to avoid mitochondrial side effects It is a deep

and thoughtful resource that will appeal to basic scientists,

clinicians, and professional drug developers

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants provides ample reminders of

the intimate connections between mitochondria, phar‑

macology, and toxicology Some of the most widely used

tool compounds for investigating mitochondrial

physiology, such as antimycin and oligomycin, are indeed

natural products that serve as a chemical warfare in the

microbial world The fact that antimicrobial agents are

often toxic to mitochondria is not surprising given the

hypothesized proto‐bacterial origin of mitochondria

These overlapping effects of such drugs are perhaps best

illustrated by aminoglycosides and linezolid antibiotics, which not only inhibit bacterial protein synthesis but are also well known to cause neurotoxicity such as hearing loss, peripheral neuropathy, and optic neuropathy through impairment of mitochondrial translation

Pharmacogenetics contributes to these toxicities with the well‐established link between the m.1555A>G variant that predisposes to aminoglycoside‐induced deafness

Toxic side effects of clinically important and investiga‑

tional new drugs for viruses have historically provided fundamentally new insights into the replication of mtDNA One of the earliest anti‐HIV agents, zidovudine (azidothymidine (AZT)), is a nucleoside analogue that effectively inhibits viral reverse transcriptase but, in some patients, inhibits the mitochondrial polymerase gamma, leading to depletion of mtDNA particularly in muscle and causing myopathic weakness These mito‑

chondrial toxicities exposed the reliance and vulnerabil‑

ity of the mitochondrial genome to disruptions of the deoxynucleotide pool substrates for mtDNA replication

These toxicities also serve as a reminder that the mtDNA replication machinery of mitochondria actually resem‑

bles that of viruses

Mitochondrial toxicity is such a common side effect in humans; a thorough understanding and surveillance of these off‐target effects are required for the successful development of new medicines A vivid case in point is fialuridine or 1‐(2‐deoxy‐2‐fluoro‐1‐d‐arabinofuranosyl)‐

5‐iodouracil (FIAU), a nucleoside analogue that was tested for therapeutic efficacy for hepatitis B infection but tragi‑

cally caused fatal liver failure and death in 5 of 15 patients and forced liver transplantations in two other patients

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants takes a rather systematic

approach to mitochondrial pharmacology and toxicology and for this reason will be of use to even those outside of strict drug discovery It begins with a scholarly introduc‑

tion to the nuances of mitochondrial drug transport and detoxification systems, illustrated with specific case stud‑

ies (Chapters 1–5) It then reviews cardinal features of mitochondrial toxicity at the organ level, highlighting some

of the dose‐limiting toxicities of very commonly used

Foreword

Trang 28

xxx Foreword

and lifesaving drugs (Chapter 6–12) One of the greatest

challenges in our field lies in measuring mitochondrial

function Mitochondrial Dysfunction Caused by Drugs

and Environmental Toxicants dedicates many chapters

(Chapters 13–29) to reviewing modern technologies for

measuring mitochondrial function in vitro, ex vivo, and

in vivo Although these technologies represent the cur‑

rent state of the art, they have their limitations, and

much research is required to pioneer new, facile bio‑

markers and technologies that are sensitive, specific,

and minimally invasive The text then progresses to

reports from the clinic (Chapters 30–40) as well as from

environmental biology (Chapters 41–45) that offer addi‑

tional vignettes and examples of drug–mitochondria

interactions

The book Mitochondrial Dysfunction Caused by

Drugs and Environmental Toxicants is very timely

While genetics and genomics have driven much pro‑

gress in mitochondrial medicine for the past few dec‑

ades, we anticipate that chemical biology may represent one of the most exciting new frontiers We applaud Yvonne Will, James Dykens, and all of their contribu‑

tors for assembling this new two volume book enti‑

tled: Mitochondrial Dysfunction Caused by Drugs

and Environmental Toxicants This textbook will be an

important canon in the future of mitochondrial medi‑

cine and more broadly in modern drug discovery

Vamsi Mootha, M.D (Boston, MA)

and Michio Hirano, M.D (New York, NY)

Trang 29

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

Trang 30

Mitochondrial Dysfunction Caused by Drugs

and Environmental Toxicants

Volume II

Edited by

Yvonne Will, PhD, ATS Fellow

Pfizer Drug Safety R&D, Groton, CT, USA

James A Dykens

Eyecyte Therapeutics

Califormia, USA

Trang 31

This edition first published 2018

All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Yvonne Will and James A Dykens to be identified as the editors of this work has been asserted in accordance with law.

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John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA

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Library of Congress Cataloging‐in‐Publication Data

Names: Will, Yvonne, editor | Dykens, James Alan, 1951– editor.

Title: Mitochondrial dysfunction caused by drugs and environmental toxicants /

edited by Yvonne Will, James A Dykens.

Description: Hoboken, NJ : John Wiley & Sons, 2018 | Includes bibliographical references and index |

Identifiers: LCCN 2017046043 (print) | LCCN 2017048850 (ebook) | ISBN 9781119329732 (pdf) |

ISBN 9781119329749 (epub) | ISBN 9781119329701 (cloth)

Subjects: LCSH: Drugs–Toxicology | Mitochondrial pathology.

Classification: LCC RA1238 (ebook) | LCC RA1238 M58 2018 (print) | DDC 615.9/02–dc23

LC record available at https://lccn.loc.gov/2017046043

Cover Design: Wiley

Cover Image: Courtesy of Sylvain Loric

Set in 10/12pt Warnock by SPi Global, Pondicherry, India

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

Trang 32

Contents

List of Contributors xiii

Foreword xxv

Part 4 Reports from the Clinic 457

30 Statin and Fibrate‐Induced Dichotomy of Mitochondrial Function 459

Viruna Neergheen, Alex Dyson, Luke Wainwright, and Iain P Hargreaves

30.2 Statins 460

30.3 Effect of Statin Treatment on Endogenous CoQ10 Status 460

30.4 Effect of Statin Treatment on Cerebral CoQ10 Status 462

30.5 Effect of Statin Treatment on Oxidative Phosphorylation 463

30.5.1 Impairment of Isoprenylation 463

30.5.2 Uncoupling Oxidative Phosphorylation 464

30.5.3 Direct Interaction with the Enzyme Complexes of the Oxidative Phosphorylation System 464

30.5.4 Oxidative Stress 465

30.5.5 Statin Lactones 465

30.5.6 Mitochondrial Biogenesis 466

30.6 Fibrates 467

30.7 The Effect of Fibrate Treatment on Mitochondrial Respiratory Chain Function 467

30.8 Fibrates in the Treatment of Oxidative Phosphorylation Defects 468

References 469

31 Friend or Foe: Can Mitochondrial Toxins Lead to Similar Benefits as Exercise? 475

Sofia Annis, Adeel Safdar, Eduardo Biala, Ayesha Saleem, Housaiyin Li, Priya Gandhi, Zoe Fleischmann,

Carmen Castaneda‐Sceppa, Jonathan L Tilly, Dori C Woods, and Konstantin Khrapko

31.1 Beneficial Effects of ROS and Mitotoxin Exposure 475

31.2 Window of Opportunity for ROS and Mitotoxins: Low Concentration and Short Time 476

31.3 Endurance Exercise, a Greatly Beneficial, Transient ROS‐Generating Activity, Causes

Translocation of p53 to Mitochondria 477

31.4 Mild Exposure to Mitochondrial Toxins In Vitro Recapitulates a Beneficial Endpoint of

Endurance Exercise (Translocation of p53 to Mitochondria) 477

31.5 Progeroid mtDNA Mutator Mouse: A Test Ground for the Similarity between the Effects of Mitotoxin

Exposure and Exercise 478

31.6 Mutational Analysis Hints Existence of the “Good” and the “Bad” mtDNA and Evokes Alternative

Hypotheses 478

31.6.1 Mitotoxins May Ameliorate Accumulation of mtDNA Damage by Alteration of Mitochondrial Dynamics

and Activation of Mitophagy Resulting in Removal of the “Bad” Mitochondria 479

31.6.2 Mitotoxins May Ameliorate Accumulation of mtDNA Damage by Activating Mitochondria‐Derived Vesicle

Trafficking and/or by Formation of Mitochondrial Spheroids 480

Trang 33

vi

31.7 Ab Absurdo: Lack of Exercise May Result in Increased Damage 480

31.8 Conclusions, Disclaimers, and Perspectives 480

32.2 The Tricarboxylic Acid Cycle as a Target Pathway 488

32.3 Effects on the Mitochondrial Electron Transport Chain 490

32.4 Drugs of Abuse Might Target Mitochondrial Biogenesis 493

32.5 Mitochondrial Quality Control and Drugs of Abuse 495

32.6 Mitochondrial Fusion/Fission Equilibrium Is Affected by Drugs of Abuse 496

32.7 Mitochondrial Distribution under the Influence of Drugs of Abuse 498

References 501

33 Drug‐Induced Mitochondrial Toxicity during Pregnancy 509

Diana Luz Juárez-Flores, Ana Sandra Hernández, Laura Garcia, Mariona Guitart‐Mampel, Marc Catalán‐Garcia, Ingrid González‐Casacuberta, Jose César Milisenda, Josep Maria Grau, Francesc Cardellach, Constanza Morén, and Glòria Garrabou

33.1 Mitochondria in Human Fertility 510

33.2 Mitochondrial Toxicity in Human Pregnancy 510

33.2.1 Risk Categories of Mitochondrial Toxic Drugs According to their Capacity to Cause Birth Defects during

Pregnancy 510

33.2.2 Clinical Spectrum of Mitochondrial Toxicity during Pregnancy 512

33.2.3 Classes of Mitochondrial Toxic Drugs Administered during Pregnancy 512

34 Mitochondrial Toxicity in Children and Adolescents Exposed to Antiretroviral Therapy 521

Antoni Noguera‐Julian, Eneritz Velasco‐Arnaiz, and Clàudia Fortuny

34.2 Mitochondrial Toxicity in Children and Adolescents Infected with HIV 522

34.3 Mitochondrial Toxicity in HIV‐Uninfected Infants That Were Perinatally Exposed to Antiretrovirals 524

References 525

35 Drug‐Induced Mitochondrial Cardiomyopathy and Cardiovascular Risks in Children 529

Neha Bansal, Mariana Gerschenson, Tracie L Miller, Stephen E Sallan, Jason Czachor, Hiedy Razoky, Ashley Hill, Miriam Mestre, and Steven E Lipshultz

35.2 HIV Therapy 529

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36 Role of Mitochondrial Dysfunction in Linezolid‐Induced Lactic Acidosis 547

Alessandro Santini, Dario Ronchi, Daniela Piga, and Alessandro Protti

36.1 Mechanisms Responsible for Lactic Acidosis in Critically Ill Subjects 548

36.2 Mechanisms Responsible for Tissue Hypoxia in Critically Ill Subjects 548

36.3 Relationship between Lactic Acidosis and Oxygen‐Derived Variables 548

36.4 Incidence and Risk Factors of Linezolid‐Induced Lactic Acidosis 549

36.5 Relationship between Linezolid‐Induced Lactic Acidosis and Oxygen‐Derived Variables 552

36.6 Mitochondrial Ribosomes and Translation 552

36.7 How Linezolid Exerts its Therapeutic—and Toxic—effects 553

36.8 Mitochondrial DNA Polymorphisms and Susceptibility to Linezolid 553

36.9 Mitochondrial Toxicity of Linezolid 555

38 Lessons Learned from a Phase I Clinical Trial of Mitochondrial Complex I Inhibition 563

Cecilia C Low Wang, Jeffrey L Galinkin, and William R Hiatt

39.4.2 Myocardial Infarction (MI) 572

39.4.3 Acute Kidney Injury (AKI) 572

39.4.4 Spinal Cord Injury 572

Trang 35

40 Mitochondrial Toxicity Induced by Chemotherapeutic Drugs 593

Luciana L Ferreira, Ana Raquel Coelho, Paulo J Oliveira, and Teresa Cunha‐Oliveira

40.2 Mitochondria and Cancer Chemotherapy 593

40.3 Conventional Chemotherapeutic Agents and Mitochondria 594

40.3.6.3 Tyrosine Kinase Inhibitors 602

40.3.7 Estrogen Receptor Modulators 602

40.4 Mitoprotectants as Adjuvants in Chemotherapy 603

References 605

Part 5 Environmental Toxicants and Mitochondria 613

41 The Mitochondrial Exposome 615

Douglas I Walker, Kurt D Pennell, and Dean P Jones

41.1.1 The Human Exposome 615

41.1.2 The Mitochondrial Exposome 616

41.1.3 Mitochondrial DNA Adductome 616

41.1.4 Mitochondrial Genome and Proteome 617

41.2 Environmental Pollutants and Mitochondrial Toxicity 617

41.2.1 Polycyclic Aromatic Hydrocarbons 618

41.2.2 Organohalogens 618

41.2.3 Contemporary Pesticides 619

41.2.4 High‐Throughput Screening for Mitochondrial Toxicants 619

41.3 Bioaccumulation of Environmental Pollutants 620

41.4 Mitochondria High‐Resolution Metabolomics 622

41.4.1 High‐Resolution Metabolomics 622

41.4.2 Metabolic Phenotyping of Intact Mitochondria 623

41.5 Case Study: Profiling the Human Mitochondrial Exposome 625

41.5.1 Adrenal Glands 625

41.5.2 Methods 626

41.5.2.1 Adrenal Gland Selection Criteria and Procurement 626

41.5.2.2 Adrenal Gland Tissue Preparation 626

41.5.2.3 Mitochondria Isolation and Sample Preparation 627

Trang 36

41.5.3.3 High‐Resolution Metabolomics Results 628

41.5.3.4 Characterizing the Mitochondrial Exposome 628

41.5.3.5 Case Study Conclusions 630

References 632

42 Central Mitochondrial Signaling Mechanisms in Response to Environmental Agents:

Integrated Omics for Visualization 639

Young‐Mi Go, Karan Uppal, and Dean P Jones

42.2 High‐Resolution Metabolomics 641

42.3 High‐Resolution Metabolomics of Liver Mitochondria 642

42.4 Integration of Mitochondrial Redox Proteomics and Metabolomics: RMWAS 643

42.5 Integration of HRM with Transcriptomics: TMWAS 645

42.6 Three‐Way Integration of Redox Proteomics, Metabolomics, and Transcriptomics to Create RMT

Association Study for Mitochondrial Signaling in Manganese (Mn) Toxicity 645

42.7 Integrated Omics Applications in Mitochondrial Metabolic Disorder: Fatty Liver, Diabetes, Obesity, and

Neurodegenerative Diseases 648

42.8 Summary and Perspective 649

References 650

43 Detection of Mitochondrial Toxicity of Environmental Pollutants Using Caenorhabditis elegans 655

Laura L Maurer, Anthony L Luz, and Joel N Meyer

43.1 What We Know about Pollutant Influences on Mitochondria 655

43.1.1 Introduction 655

43.1.2 Environmental Mitotoxicants 657

43.1.3 How Should We Prioritize Environmental Chemicals and Stressors for Mitotoxicity Testing? 658

43.1.4 Mechanistic Organization of Mitotoxic Effects 658

43.1.5 Testing Environmental Chemicals and Stressors for Mitotoxicity: Approaches and Considerations 659

43.2 Advantages of the Caenorhabditis elegans Model 660

43.2.1 Introduction 660

43.2.2 C elegans Biology 661

43.2.3 Mitochondrial Biology in C elegans 661

43.2.4 Mutagenesis and Mutant Availability 662

43.2.5 RNA Interference 662

43.2.6 DNA Transformation 663

43.2.7 C Elegans: A Model of Expanding Utility in Toxicology 663

43.3 Limitations of C elegans for Studying Mitochondrial Toxicity 663

43.3.5 Concluding Remarks on Limitations of C elegans as a Model Organism 666

43.4 Methods for Assessing Mitochondrial Toxicity in C Elegans 667

Trang 37

43.4.4 Steady‐State ATP Levels 668

43.4.5 Transcriptomics, Proteomics, and Metabolomics 668

43.5.2 Contributions of C elegans in Discovering Key Mitochondrial Roles in Neurotoxicity 671

43.5.3 General Stress Response Mechanisms Important for Mitigating Mitochondrial Toxicity and Promoting

Healthspan: Discoveries in C elegans 672

43.5.4 Emerging Roles for C elegans in Investigating Environmental Mitotoxicants 672

References 673

44 Persistent Organic Pollutants, Mitochondrial Dysfunction, and Metabolic Syndrome 691

Hong Kyu Lee and Youngmi Kim Pak

44.2 Health Hazard of Environmental Chemicals: A Short History 691

44.3 Low‐Level Exposure to Multiple Chemicals 692

44.4 POPs and Obesity Paradox 692

44.5 Body Burden of Chemicals 693

44.6 Diabetes Mellitus, Insulin Resistance, and Metabolic Syndrome 693

44.7 Association of POPs with Diabetes and Metabolic Syndrome 695

44.7.1 Ecological Studies 695

44.7.2 Epidemiologic Studies on the Association between POPs and T2DM 695

44.7.3 Animal Experiments: Low‐Dose Exposure to Chemicals and Development of Diabetes 696

44.7.4 Cause–Effect Relationship between Exposure to POPs and the Onset of T2DM or MetS 696

44.8 Toxic and Biological Effects of Some POPs via AhR 696

44.9 Insulin Resistance and Mitochondrial Dysfunction 698

44.9.1 Mitochondrial Damages Induced by Environmental Chemicals 699

44.9.2 Scaling Law and Mitochondria 700

44.10 Measurement of POPs 702

44.10.1 Instrumental Analysis for POPs 702

44.10.2 Cell‐Based Assays for POPs 702

44.10.3 Association between CALA‐Determined Serum POP Levels and Mitochondria Inhibitor Activity 702

44.11 Summary 703

References 703

45 Cigarette Smoke and Mitochondrial Damage 709

Jalal Pourahmad, Marjan Aghvami, Mohammad Hadi Zarei, and Parvaneh Naserzadeh

45.2 Cigarette Smoke Components and Mitochondrial Toxicity 709

45.3 Health Problems Caused by Cigarette Smoking 711

45.4 Cigarette Smoke and Mitochondrial Damage in Different Disease 712

45.4.1 Cardiovascular Disease 712

45.4.1.1 Endothelial Superoxide Anion 714

45.4.2 Brain Related Diseases 714

45.4.3 Respiratory System‐Related Diseases 715

45.4.3.1 Cigarette Smoke‐Induced Mitochondrial Damage in Airway Smooth Muscle 715

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Contents xi

45.4.3.2 Effects of Cigarette Smoke Extract on Alveolar Epithelial Cells 716

45.4.3.3 Cigarette Smoke Effect on Mitochondrial Respiratory Chain 716

45.4.3.4 Cigarette Smoke Effects on Mitochondrial in Alveolar Epithelial Cells 717

45.4.3.5 Aryl Hydrocarbon Receptor and Cigarette Smoke‐Induced Mitochondrial Dysfunction 717

45.4.4 Cigarette Smoke Damage on Mitochondria in the Retinal Cells 717

45.4.5 Cigarette Smoke Induce Mitochondrial Damage in Blood Cells 717

45.4.6 Mitochondrial Damage by Cigarette Smoke Results in Cancer 718

45.5 Summary 719

References 719

Index 727

Trang 39

List of Contributors

Sandra Amaral

Daniel José Barbosa

Cell Division Mechanisms GroupInstituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto

PortoPortugal

Maria de Lourdes Bastos

Trang 40

Department of Drug Discovery and Biomedical

Sciences, College of Graduate Studies

Charleston, SC

USA

João Paulo Capela

Universidade do Portoand

FP‑ENAS (Unidade de Investigação UFP em Energia, Ambiente e Saúde), CEBIMED (Centro de Estudos em Biomedicina), Faculdade de Ciências da Saúde

Universidade Fernando PessoaPorto

Portugal

Francesc Cardellach

Félix Carvalho

Marc Catalán-García

Muscle Research and Mitochondrial Function Laboratory, Cellex‐IDIBAPS, Faculty of Medicine and Health Science‐University of Barcelona, Internal Medicine Department‐Hospital Clínic of Barcelona (HCB)

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