mitochondria and their role in cardiovascular disease || || front_matter

Mitochondria and Their Role in Cardiovascular Disease

Mitochondria and Their Role in Cardiovascular Disease

By

José Marín-García, M.D.Director, The Molecular Cardiology and NeuromuscularInstitute, Highland Park, NJ, USA

With contributions by

Alexander Akhmedov, Ph.D. and Vitalyi Rybin, Ph.D.Senior Research Scientist, The Molecular Cardiology and Neuromuscular Institute, Highland Park, NJ, USA

Gordon W. Moe, M.D.Professor, Department of Medicine, University of Toronto, St. Michael Hospital, Toronto, Canada

ISBN 978-1-4614-4598-2 ISBN 978-1-4614-4599-9 (eBook) DOI 10.1007/978-1-4614-4599-9 Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2012948132

© Springer Science+Business Media New York 2013 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, speci fi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on micro fi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied speci fi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a speci fi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

José Marín-García, M.D. The Molecular Cardiology

and Neuromuscular InstituteHighland Park, NJ, USA

To my wife Danièle, and daughter Mèlanie with love

vii

ART WORKS for Mitochondria and Their Role in Cardiovascular Disease

ART Fig #1

“signaling the mitochondria” Danièle M. Marin

ART Fig #2

“clustered mitochondria” Danièle M. Marin

viii ART WORKS for Mitochondria and Their Role in Cardiovascular Disease

ART Fig #3

“Fision and Fusion” Danièle M. Marin

ART Fig #4

“Megamitochondrion” Danièle M. Marin

ix

Preface

Over the past two decades, due to dramatic advances in molecular and cell biology, biochemistry, and genetics our view on mitochondria as a relatively static cellular powerhouse has changed radically. We now know that these organelles play a critical role in the normal and in the damaged heart as a highly dynamic integrator of energy production, in diverse signaling pathways, intrac-ellular Ca 2+ homeostasis, cell survival, and cell death. Although all of these functions are essen-tial for virtually all human organs, they are particularly important for the heart, in order to maintain its permanent rhythmic contraction and ensure oxygenation of all the body tissues. Also, mitochondrial non-bioenergetic, biogenetic, and degradation pathways are very important since understanding of these pathways and the effects that mitochondrial changes have in cardiac pathology are critical for diagnosis and treatment of mitochondrial-based cardiac diseases.

This book begins with a general introduction to mitochondria, followed by laboratory meth-ods to study the structure and function of the organelle, regulation of replication and biogen-esis, and the mechanisms and functional consequences of mitophagia and mitochondrial dynamics. Subsequent chapters deal with mitochondrial oxidative stress and the role that the organelle plays in cell signaling and cell death. Readers will learn that mitochondria have their own DNA and that mitochondrial gene mutations occur at a much faster rate than those in the nucleus. This high mutation rate of the mitochondrial DNA is behind the heart ageing pro-cesses as well as on the changes in other degenerative diseases.

Discussions will be undertaken on the biochemistry of mitochondrial cell signaling, includ-ing the nature of the proteins engaged in these processes, many of them only recently discov-ered. Besides their implication in cardiovascular pathology, mitochondria are also involved in degenerative diseases such as Parkinson’s, Huntington’s disease, cancer, and ageing. Mitochondrial mutations and their consequences in ageing and other phenotypic manifesta-tions are discussed in the following sections, and how mitochondrial proteins might constitute important targets in an attempt to develop therapeutic compounds that can regulate their func-tion. In later chapters we examine the role of mitochondria and mitochondrial abnormalities in cardiovascular diseases—their diagnosis, therapeutic options currently available, animal mod-els of mitochondrial disease, and new frontiers in mitochondria cardiovascular medicine, including areas of research that are relatively new or developing, such as proteomics, next-generation sequencing, and systems biology.

It is our hope that the information provided in this book will be useful to the clinician and student interested in clinical and basic cardiovascular research; new advances in our under-standing of cardiovascular pathophysiology will open new ways to slow the progression of failure of the injured heart and allow a better and longer active life to us all.

Virtually, from the beginning of life… Mitochondria and eukaryotes have been joined together…… Together they may continue forever and ever

Highland Park, NJ, USA José Marín-García, M.D.

xi

Contents

Section I General Principles of Mitochondria and the Heart

1 Introduction to Mitochondria in the Heart ......................................................... 3The Energy-Consuming Heart ................................................................................. 3The Mitochondrion: Origin, Morphology, Composition, and Dynamics ................ 3Cardiac Energy Metabolism..................................................................................... 4Mitochondrial Biogenesis ........................................................................................ 6Cardiac Mitochondria and Cell Death ..................................................................... 7Mitochondria and Ca2+ Signaling: Link Between Myocardial Contraction and Cell Death ...................................................................................... 7Mitochondrial Dysfunction Related to Cardiovascular Disorders ........................... 8References ................................................................................................................ 9

2 Methods to Study Mitochondrial Structure and Function ................................ 13Introduction .............................................................................................................. 13High-Resolution Imaging of Mitochondria in Live Cells ........................................ 13High-Resolution Electron Microscopy and Electron Tomography .......................... 14Molecular Biological and Biochemical Methods .................................................... 15

mtDNA Analysis ................................................................................................. 15In Vitro Assessment of Mitochondrial Function ................................................. 15In Vivo Assessment of Mitochondrial Function ................................................. 16Electrophoretic Techniques to Study Mitochondria ............................................ 18Mitochondrial Proteomics ................................................................................... 19

Transgenic Models for Assessing Mitochondrial Function in the Heart ................. 20Conclusion and Future Progress .............................................................................. 20Summary .................................................................................................................. 22References ................................................................................................................ 23

3 Mitochondrial Structure, Composition, and Dynamics ..................................... 29Introduction .............................................................................................................. 29Mitochondrial Arrangement in Cardiomyocytes ..................................................... 29Internal Structure of Mitochondria .......................................................................... 30

Mitochondrial Outer and Inner Membranes ........................................................ 31Cardiolipin........................................................................................................... 32Mitochondrial Permeability Transition Pore ....................................................... 33Voltage-Dependent Anion Channel ..................................................................... 34Adenine Nucleotide Translocase ......................................................................... 34Cyclophilin-D ...................................................................................................... 35Mitochondrial Phosphate Carrier (PiC) .............................................................. 35

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Mitochondrial Channels ...................................................................................... 36Mitochondrial Ca2+ Channels .............................................................................. 36Mitochondrial K+ Channels ................................................................................. 36mitoK

ATP Channel ................................................................................................ 37

mitoBKCa

Channel ............................................................................................... 38mitoK

V1.3 Channel.............................................................................................. 38

Mitochondrial Protein Import Channels.............................................................. 38TOM .................................................................................................................... 39Presequence Translocase in the MIM (TIM23) .................................................. 39Carrier Translocase in the MIM (TIM22) ........................................................... 40Mitochondrial Matrix and Intermembrane Space ............................................... 40

Mitochondrial Dynamics ......................................................................................... 40The Molecular Machinery and Mechanisms of Mitochondrial Fusion ............... 40The Molecular Machinery and Mechanisms of Mitochondrial Fission .............. 42Mitochondrial Trafficking ................................................................................... 43Regulation of Mitochondrial Dynamics .............................................................. 43

Conclusions .............................................................................................................. 45Summary .................................................................................................................. 46References ................................................................................................................ 49

4 Mitochondrial Biogenesis ...................................................................................... 59Introduction .............................................................................................................. 59Mitochondrial Genome: Structure and Dynamics ................................................... 59

Mitochondrial DNA ............................................................................................ 59Mitochondrial Nucleoid ...................................................................................... 60Replication of Mitochondrial DNA ..................................................................... 62Transcription of Mitochondrial DNA .................................................................. 65Translation in Mitochondria ................................................................................ 67Mitochondrial DNA Repair ................................................................................. 69

Mitochondrial Protein Biogenesis ............................................................................ 70Presequence Pathway .......................................................................................... 70Carrier Pathway ................................................................................................... 72Redox-Regulated Import Pathway ...................................................................... 73Biogenesis of the MOM Proteins ........................................................................ 73

Mitochondrial Lipid Biogenesis .............................................................................. 75Mitochondrial Phospholipids .............................................................................. 75Mitochondrial Phospholipid Biosynthesis .......................................................... 75Mitochondrial Phospholipid Traffic .................................................................... 77

PGC-1α: A Central Regulator of Mitochondrial Biogenesis ................................... 77PGC-1 Family ..................................................................................................... 77Regulation of PGC-1α ........................................................................................ 78Transcriptional Regulation .................................................................................. 78Posttranscriptional Regulation ............................................................................ 79In Vivo Functions of PGC-1 Family Members ................................................... 80PGC-1-Mediated Regulatory Circuitry in the Heart ........................................... 81

Conclusion ............................................................................................................... 81Summary .................................................................................................................. 83References ................................................................................................................ 86

5 Mechanisms of Bioenergy Production in Mitochondria ..................................... 99Introduction .............................................................................................................. 99Pyruvate Dehydrogenase Complex .......................................................................... 99Fatty Acid Oxidation (b-Oxidation Spiral) .............................................................. 101

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Production of Reducing Equivalents: Tricarboxylic Acid Cycle ............................. 104Citrate Synthase .................................................................................................. 105Aconitase ............................................................................................................. 106Isocitrate Dehydrogenase .................................................................................... 1062-Oxoglutarate Dehydrogenase (a-Ketoglutarate Dehydrogenase) .................... 106Succinate Dehydrogenase ................................................................................... 107Fumarase ............................................................................................................. 107Malate Dehydrogenase ........................................................................................ 108

Oxidative Phosphorylation ....................................................................................... 108NADH: Ubiquinone Oxidoreductase (Complex I) .............................................. 108Succinate: Ubiquinone Oxidoreductase (Complex II) ........................................ 109Ubiquinol–Cytochrome c Oxidoreductase (Complex III, or Cytochrome bc1 Complex, or CIII) ................................................................ 110Cytochrome c Oxidase (CIV or COX) ................................................................ 111ATP Synthase (Complex V) ................................................................................ 112

Role of Mitochondrial Kinases in Energy and Nucleotide Homeostasis ................. 112Creatine Kinase ................................................................................................... 113Nucleoside Diphosphate Kinase ......................................................................... 113Adenylate Kinase ................................................................................................ 113


6 Bioenergetics Interplay Between Cardiac Mitochondria and Other Subcellular Compartments ................................................................. 123Introduction .............................................................................................................. 123

Mitochondria/Nucleus Interactions ..................................................................... 123Mitochondria/Cytosol Interactions...................................................................... 127Hormonal Regulation .......................................................................................... 131Mitochondria and Peroxisomes Interactions ....................................................... 134Role of Ca2+ Ions ................................................................................................. 134


Section II Heart Mitochondria Signal Transduction: Stem Cells

7 Endothelial Mitochondria: Contribution to Cardiovascular Function and Disease ............................................................................................. 147Introduction .............................................................................................................. 147Release of Vasodilators: Role of OXPHOS and [Ca2+]

m .......................................... 147

Role of Endothelial Mitochondria in the Generation of Reactive Oxygen Species .................................................................................... 148Role of Endothelial Mitochondria in the Generation of NO .................................... 150Endothelial Mitochondria and Apoptosis ................................................................ 151Conclusions .............................................................................................................. 152Summary .................................................................................................................. 153References ................................................................................................................ 153

8 Heart Mitochondria: Receivers and Transmitters of Signals ............................ 157Introduction .............................................................................................................. 157Mitochondria Signaling ........................................................................................... 157

Mitochondrial Bioenergetics ............................................................................... 157Mitochondrial Biogenesis ................................................................................... 158

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Signaling at the Mitochondria .................................................................................. 159Reactive Oxygen Species Generation and Signaling .......................................... 159Mitochondrial Receptors ..................................................................................... 159Translocation of Proteins into Mitochondria ...................................................... 159Mitochondrial Retrograde Signaling ................................................................... 159Role of Calcium in Nuclear-Mitochondrial Cross Talk ...................................... 160Endoplasmic Reticulum ...................................................................................... 160

Key Players in Mitochondrial Signaling .................................................................. 160Nuclear Gene Activation ..................................................................................... 160Protein Kinases.................................................................................................... 161Calcium Signaling ............................................................................................... 162Mitochondrial K

ATP Channel ............................................................................... 163

Mitochondrial Permeability Transition Pore ....................................................... 164Survival and Stress Signals Impact Heart Mitochondria ......................................... 165

Survival Signals ................................................................................................... 165Stress Signals ...................................................................................................... 167

Metabolic Signals and UCPs ................................................................................... 167Cardiomyopathy and Mitochondrial Signaling Defects .......................................... 170Mitochondrial Signaling in Myocardial Ischemia and Cardioprotection ................ 170Mitochondrial Signaling and Myocardial Hypertrophy ........................................... 173

Survival Signals/Apoptosis ................................................................................. 174Future Prospects: Therapeutic Targets and Directions............................................. 174Conclusions .............................................................................................................. 175Summary .................................................................................................................. 175References ................................................................................................................ 176

9 Stem Cells and Mitochondria ............................................................................... 183Introduction .............................................................................................................. 183Stem Cell Types and Delivery Techniques .............................................................. 183

Allogenic Cell Types ........................................................................................... 184Mechanisms of Stem Cell Self-Renewal and Pluripotency ..................................... 187

Cell Cycle Regulation and Self-Renewal of Stem Cells ..................................... 187Molecular Circuit of Pluripotency ...................................................................... 188

Mitochondrial Metabolism in Stem Cells ................................................................ 190Mitochondria Number and Morphology ............................................................. 190Mitochondrial DNA Dynamics ........................................................................... 190Mitochondrial Metabolism .................................................................................. 190Oxidative Stress in Stem Cells ............................................................................ 191Mitochondria-Mediated Apoptosis of Stem Cells............................................... 191


Section III Stress and Cell Death

10 Heart Mitochondrial ROS and Oxidative Stress ................................................. 205Introduction .............................................................................................................. 205Mitochondrial ROS Production ............................................................................... 205Effects of ROS on Cardiomyocytes ......................................................................... 207ROS and Cell Signaling ........................................................................................... 207ROS and Cardiac Pathology ..................................................................................... 207Oxidative Stress in Myocardial Ischemia and HF ................................................... 210ROS in the Aging Heart ........................................................................................... 211

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Oxidative Stress and Apoptosis ............................................................................... 214Mitochondrial Nitric Oxide ...................................................................................... 214Antioxidant Defenses ............................................................................................... 215Antioxidant Therapy ................................................................................................ 216Conclusions and Future Directions .......................................................................... 218Summary .................................................................................................................. 218References ................................................................................................................ 219

11 Cell-Death Pathways and Mitochondria .............................................................. 225Introduction .............................................................................................................. 225Apoptosis ................................................................................................................. 225

Intrinsic (Mitochondrial) Pathway ...................................................................... 225Extrinsic Pathway ................................................................................................ 229

Necrosis .................................................................................................................... 230Autophagy ................................................................................................................ 231Cell Death in the Pathogenesis of Myocardial Disorders ........................................ 233Conclusions .............................................................................................................. 234Summary .................................................................................................................. 235References ................................................................................................................ 237

Section IV Mitochondria in Pediatric Cardiology

12 Mitochondria in Pediatric Cardiovascular Diseases ........................................... 245Introduction .............................................................................................................. 245General Aspects of Mitochondria ............................................................................ 245Mitochondrial Cardiomyopathy ............................................................................... 247

Cardioneuropathies and Mitochondrial Phenotype ............................................. 250Diagnosis .................................................................................................................. 252

Clinical and Laboratory Findings in MCM ......................................................... 252Histological and Electron Microscopic (EM) Analysis ...................................... 252Mitochondrial tRNA Mutations .......................................................................... 256

Mitochondrial Structural Gene Mutations ............................................................... 257ATP Synthase (ATPase6) .................................................................................... 257Cytochrome b ...................................................................................................... 258Mutations in COX and ND Subunits ................................................................... 258MtDNA Depletion ............................................................................................... 258

Mitochondrial Changes in Congenital Heart Defects .............................................. 259Structural and Functional Cardiac Defects ......................................................... 259Cardiac Dysrhythmias ......................................................................................... 259Other Congenital Cardiomyopathies with Mitochondrial Defects...................... 260Congenital Heart Defects and Mitochondrial Function ...................................... 262

Conclusions and Future Directions .......................................................................... 262Summary .................................................................................................................. 263References ................................................................................................................ 265

Section V The Aging Heart and Mitochondria

13 Mitochondria in the Aging Heart ......................................................................... 273Introduction .............................................................................................................. 273Oxidative Stress and Aging ...................................................................................... 273Oxidative Damage of Mitochondrial Proteins in Aging Heart ................................ 275Role of Lipids in Age-Related Changes of Cardiac Mitochondria .......................... 275Involvement of DNA Damage in Age-Related Mitochondrial Dysfunction ........... 278

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Loss of Cardiac Cells due to Chronic Exposure to Free Radicals in the Senescent Myocardium .................................................................................. 279Aging and Biogenesis of Mitochondria ................................................................... 280Mitochondrial Dynamics in Aging .......................................................................... 281Telomeres ................................................................................................................. 281Cardiac Channelopathies ......................................................................................... 282Conclusions .............................................................................................................. 284Summary .................................................................................................................. 284References ................................................................................................................ 286

Section VI Mitochondria in Atherosclerosis, Hypertension and Ischemia

14 The Role of Mitochondria in Atherosclerosis ...................................................... 295Introduction .............................................................................................................. 295Mitochondrial Dysfunction in Atherosclerosis ........................................................ 295

Oxidative Dysfunction ........................................................................................ 295Oxidative Damage ............................................................................................... 297

Mitochondrial Dysfunction in Conditions Associated with Atherosclerosis ........... 298Diabetes Mellitus ................................................................................................ 298Dyslipidemia ....................................................................................................... 299


15 The Role of Mitochondria in Hypertension ......................................................... 305Introduction .............................................................................................................. 305Mechanisms of ROS Generation and Mitochondrial Dysfunction .......................... 305The Role of Mitochondrial Uncoupling Proteins ..................................................... 307The Mitochondrial DNA and Oxidative Damage .................................................... 308Conclusions and Future Prospects ........................................................................... 309Summary .................................................................................................................. 309References ................................................................................................................ 310

16 Role of Mitochondria in Ischemia and Cardioprotection .................................. 313Introduction .............................................................................................................. 313Mitochondria in Ischemia and Reperfusion in the Heart ......................................... 313Impairment of Energy Metabolism .......................................................................... 313Impairment of Oxidative Metabolism ...................................................................... 314Alterations in Mitochondrial Calcium Homeostasis ................................................ 315Increased Generation of Reactive Oxygen Species ................................................. 315Mitochondrial Permeability Transition Pore Opening ............................................. 315ATP-Binding Cassette Mitochondrial Erythroid ...................................................... 317Mitochondria and Cardioprotection ......................................................................... 317Mitochondria Self-Defense Mechanisms ................................................................. 317Mitochondria-Directed Cardioprotection Strategies ................................................ 318

MPTP Inhibition.................................................................................................. 318Antioxidant and Inhibition of Monoamine Oxidase ........................................... 319Metabolic Approaches ........................................................................................ 319Thioredoxin/Thioredoxin Reductase System ...................................................... 320


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Section VII Mitochondria in Heart Failure and Dysrhythmias

17 Mitochondrial Dynamics in Health and Disease ................................................. 329Introduction .............................................................................................................. 329Mitochondrial Dynamics in Human Pathology ....................................................... 329

Autosomal Dominant Optic Atrophy .................................................................. 330Charcot-Marie-Tooth Neuropathy ....................................................................... 330Charcot-Marie-Tooth Neuropathy Type 2A ........................................................ 330Charcot-Marie-Tooth Neuropathy Type 4A ........................................................ 330Abnormal Brain Development ............................................................................ 330The Wolf-Hirschhorn Syndrome ......................................................................... 331Obesity and Type 2 Diabetes ............................................................................... 332Mitochondrial Dynamics in the Normal and Failing Heart ................................ 332Ischemia/Reperfusion Injury ............................................................................... 333Cardiomyopathies ............................................................................................... 334Heart Failure ........................................................................................................ 334Diabetic Heart ..................................................................................................... 335


18 Mitochondria Play an Essential Role in Heart Failure ...................................... 343Introduction .............................................................................................................. 343Mitochondrial Bioenergetics in HF.......................................................................... 343

ATP Generation ................................................................................................... 343Mitochondrial ROS Generation and Antioxidant Response ............................... 346

Critical Role of Mitochondrial Bioenergetic Enzymes and ROS in Animal Models of HF ........................................................................... 348Electron Transport Chain Respirasome in HF ......................................................... 350Transgenic Models in the Study of Mitochondria Alterations in Heart Failure ..................................................................................... 354

Mitochondrial DNA and HF in Transgenic Mice ............................................... 356Peroxisome Proliferator-Activated Receptors-γ Coactivator 1 (PGC-1a) ............... 357

Peroxisome Proliferator-Activated Receptors ..................................................... 359Defects in Cytosolic Proteins Can Cause HF with Mitochondrial Dysfunction ......................................................................... 361

Calcium Signaling and Mitochondrial Function in HF............................................ 361Mitochondrial Function and Apoptosis in HF ......................................................... 362Mitochondrial Dynamics Function and Dysfunction in HF .................................... 362Conclusions and Future Prospect ............................................................................. 362Summary .................................................................................................................. 364References ................................................................................................................ 366

19 Mitochondria and Cardiac Dysrhythmias ........................................................... 371Introduction .............................................................................................................. 371The Role of Sarcolemmal K

ATP Channels in Dysrhythmia ...................................... 371

Metabolic Alterations ............................................................................................... 372Permeability Transitional Pore ............................................................................ 373

The Inner Membrane Anion Channel ...................................................................... 374The Mitochondrial K

ATP Channels............................................................................ 375

The Mitochondrial Calcium Uniporter................................................................ 376Mitochondrial Redox Status .................................................................................... 377Conclusions .............................................................................................................. 378Summary .................................................................................................................. 378References ................................................................................................................ 379

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Section VIII Mitochondria in Heart Metabolism

20 Diabetes and Cardiac Mitochondria .................................................................... 387Introduction .............................................................................................................. 387Diabetes-Related Alterations in the Mitochondrial Metabolic Milieu .................... 387Role of Mitochondria-Derived ROS in Diabetic Myocardium ................................ 390Apoptosis ................................................................................................................. 391Mitochondria and Activation of Metabolic Damaging Pathways ............................ 391Diabetes and Cardiac Mitochondrial Calcium Handling ......................................... 393Maternally Inherited Diabetes and Deafness ........................................................... 393Conclusions .............................................................................................................. 393Summary .................................................................................................................. 395References ................................................................................................................ 396

21 The Role of Mitochondria in the Metabolic Syndrome and Insulin Resistance ........................................................................................... 401Introduction .............................................................................................................. 401Mechanistic Development of Insulin Resistance: The Role of Mitochondria ........................................................................................ 401Oxidative Stress and Mitochondrial Function ......................................................... 403Insulin Resistance and Mitochondrial Biogenesis ................................................... 403Aging and Mitochondrial Function .......................................................................... 405Genetic Factors and Mitochondrial Function .......................................................... 405Cardiovascular Metabolic Syndrome: Mitochondrial Bioenergetics and Biogenesis Defects ..................................................................... 406Conclusions .............................................................................................................. 408Summary .................................................................................................................. 408References ................................................................................................................ 409

22 Thyroid Hormone and Myocardial Mitochondria .............................................. 413Introduction .............................................................................................................. 413Thyroid Hormone: Mechanisms of Regulation of Cardiac Mitochondria .......................................................................................... 413

Genomic Actions of Thyroid Hormone: Regulation of Expression of Nuclear-Encoded Mitochondrial Proteins....................................................... 413Thyroid Hormone Regulates Expression of Mitochondria-Encoded Proteins ..................................................................... 415Thyroid Hormone as a Nongenomic Regulator of Mitochondrial Protein/Enzyme Activities ...................................................... 416

Thyroid Hormone and Bioenergetics: Regulation of Mitochondrial Energy Production.................................................................................................... 416Thyroid Hormone and Mitochondrial Biogenesis ................................................... 419Thyroid Hormone-Dependent Myocardial Hypertrophy and Mitochondria ................................................................................ 421Mitochondria Dynamics and Thyroid Hormones ..................................................... 421Conclusions .............................................................................................................. 422Summary .................................................................................................................. 422References ................................................................................................................ 423

Section IX Mitochondrial Therapy

23 Targeting the Mitochondria in Cardiovascular Diseases ................................... 431Introduction .............................................................................................................. 431Treatment of Mitochondrial Respiratory and Metabolic Defects ............................ 431

Treatment with Antioxidants ............................................................................... 432

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Antioxidant Defense in Heart Failure/ROS Regulation of Signaling Pathways ......................................................................................... 434Mitochondrial-Based Therapy of FAO Disorders, Dysrhythmias, and CHF ...................................................................................... 437Cardioprotective Agents ...................................................................................... 438

Animal Models of Mitochondrial-Based Heart Disease .......................................... 439Mitochondrial Defects and Gene Therapy ............................................................... 441

Identification of Genetic Defects ........................................................................ 441Gene Therapy ...................................................................................................... 441Targeting the Mitochondria Using Nucleic Acids ............................................... 443Alternative Methods to Target Mitochondria with Bioactive Compounds ......................................................................................... 444

Stem Cells and Mitochondrial Defects .................................................................... 444Conclusions and Future Perspectives ....................................................................... 444Summary .................................................................................................................. 445References ................................................................................................................ 447

Section X Looking to the Future of Mitochondria and the Heart

24 Current Progress and Future Perspectives: Toward Mitochondrial Medicine .......................................................................... 455Introduction .............................................................................................................. 455mtDNA Mutations .................................................................................................... 455nDNA Mutations ...................................................................................................... 457

Defects in mtDNA Dynamics ............................................................................. 457Defects in mtDNA Translation ............................................................................ 457Defects in OXPHOS Complexes ......................................................................... 457Defects in Mitochondrial Dynamics ................................................................... 458Defects in Other Nuclear Genes Controlling Mitochondrial Functions.............. 458

Models for Mitochondrial Disorders ....................................................................... 458Yeast Models ....................................................................................................... 458Cytoplasmic Hybrid (Cybrid) Models ................................................................ 458Mouse Models ..................................................................................................... 459Transmitochondrial Mice .................................................................................... 459Mouse Models with Targeted Nuclear Mitochondrial Genes ............................. 460

Diagnosis of Mitochondrial Disorders ..................................................................... 461Histological and Biochemical Screening ............................................................ 461Molecular Genetic Screening .............................................................................. 461Next-Generation Sequencing .............................................................................. 463Mitochondrial Gene Profiling: Microarray Technologies ................................... 463Mitochondrial Proteome...................................................................................... 464

Conclusions and Future Trends ................................................................................ 465Summary .................................................................................................................. 465References ................................................................................................................ 468

Glossary .......................................................................................................................... 475

Index ................................................................................................................................ 485

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