Mitochondria and the Heart

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3 Mitochondria and the Heart

4 Developments in Cardiovascular Medicine 232. A. Bayes de Luna, F. Furlanello, BJ. Maron and D.P. Zipes (eds.): Arrhythmias and Sudden Death in Athletes ISBN: X 233. J-C. Tardif and M.G. Bourassa (eds): Antioxidants and Cardiovascular Disease ISBN: J. Candell-Riera, J. Castell-Conesa, S. Aguade Bruiz (eds): Myocardium at Risk and Viable Myocardium Evaluation by SPET ISBN: M.H. Ellestad and E. Amsterdam (eds): Exercise Testing: New Concepts for the New Century ISBN: Douglas L. Mann (ed.): The Role of Inflammatory Mediators in the Failing Heart ISBN: Donald M. Bers (ed.): Excitation-Contraction Coupling and Cardiac Contractile Force, Second Edition ISBN: Brian D. Hoit, Richard A. Walsh (eds.): Cardiovascular Physiology in the Genetically Engineered Mouse, Second Edition ISBN X 239. Pieter A. Doevendans, A.A.M. Wilde (eds.): Cardiovascular Genetics for Clinicians 2001 ISBN Stephen M. Factor, Maria A.Lamberti-Abadi, Jacobo Abadi (eds.): Handbook of Pathology and Pathophysiology of Cardiovascular Disease ISBN Liong Bing Liem, Eugene Downar (eds): Progress in Catheter Ablation ISBN Pieter A. Doevendans, Stefan Kaab (eds): Cardiovascular Genomics: New Pathophysiological Concepts ISBN Daan Kromhout, Alessandro Menotti, Henry Blackburn (eds.): Prevention of Coronary Heart Disease: Diet, Lifestyle and Risk Factors in the Seven Countries Study ISBN X 244. Antonio Pacifico (ed.), Philip D. Henry, Gust H. Bardy, Martin Borggrefe, Francis E. Marchlinski, Andrea Natale, Bruce L. Wilkoff (assoc. eds): Implantable Defibrillator Therapy: A Clinical Guide ISBN Hein J.J. Wellens, Anton P.M. Gorgels, Pieter A. Doevendans (eds.): The ECG in Acute Myocardial Infarction and Unstable Angina: Diagnosis and Risk Stratification ISBN Jack Rychik, Gil Wernovsky (eds.): Hypoplastic Left Heart Syndrome ISBN Thomas H. Marwick: Stress Echocardiography. Its Role in the Diagnosis and Evaluation of Coronary Artery Disease 2nd Edition. ISBN Akira Matsumori: Cardiomyopathies and Heart Failure: Biomolecular, Infectious and Immune Mechanisms ISBN Ralph Shabetai: The Pericardium ISBN Irene D. Turpie; George A. Heckman (eds.): Aging Issues in Cardiology ISBN C.H. Peels; L.H.B. Baur (eds.): Valve Surgery at the Turn of the Millennium ISBN X 252. Jason X.-J. Yuan (ed.): Hypoxic Pulmonary Vasoconstriction: Cellular and Molecular Mechanisms ISBN Francisco J. Villarreal (ed.): Interstitial Fibrosis In Heart Failure 2004 ISBN Xander H.T. Wehrens; Andrew R. Marks (eds.): Ryanodine Receptors: Structure, function and dysfunction in clinical disease ISBN Guillem Pons-Llado; Francesc Carreras (eds.): Atlas of Practical Applications of Cardiovascular Magnetic Resonance ISBN Jose Marin-Garcia : Mitochondria and the Heart ISBN Previous volumes are still available

5 Mitochondria and the Heart Edited by Jose Marin-Garcia The Molecular Cardiology and Neuromuscular Institute, Highland Park, New Jersey Department of Physiology & Biophysics, UMDNJ-Robert Wood Johnson Medical School Piscataway, New Jersey With the collaboration of Michael J Goldenthal The Molecular Cardiology Institute, Highland Park, New Jersey 4jj Springer

6 JosÈ MarÌn-GarcÌa The Molecular Cardiology and Neuromuscular Institute Highland Park, New Jersey Department of Physiology & Biophysics UMDNJ-Robert Wood Johnson Medical School Piscataway, New Jersey Library of Congress Cataloging-in-Publication Data A C.I.P. Catalogue record for this book is available from the Library of Congress. ISBN e-isbn ISBN e-isbn Printed on acid-free paper Springer Science+Business Media, Inc. All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, Inc., 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now know or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks and similar terms, even if the are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, 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 in the United States of America SPIN springeronline.com

7 Dedication This book is dedicated to my wife, Daniele, and daughter, Melanie, with love

8 Contents 1. An Introduction to Mitochondria and the Heart Overview 1 What are mitochondria? 1 How to study mitochondria: New and old 3 Mitochondrial bioenergetics 6 Mitochondrial biogenesis 7 Cardiac mitochondrial changes during cardiac growth and development 9 Mitochondria: the primary site of ROS generation and also a critical target of its damaging effects 10 Mitochondrial dysfunction in cardiovascular disease 10 Defects in mtdna 10 Defects in nuclear-dna encoded mitochondrial proteins 12 Myocardial ischemia and ETC 13 Apoptosis and cell death 14 Animal models of mitochondrial-associated cardiovascular disease 15 Diagnosis and treatment of mitochondrial-based cardiac diseases 16 The road ahead 16 References 17

9 viii Mitochondria and the Heart 2. Mitochondrial Bioenergetics in the Heart 27 Overview 27 Introduction 27 Complex I (NADH-ubiquinone oxidoreductase) 28 Enzyme structure 29 Complex II (Succinate-ubiquinone oxidoreductase) 30 Complex III (Ubiquinol-cytochrome c oxidoreductase) 32 The Q cycle and bcl function 33 Complex IV (Cytochrome c oxidase) 35 COX enzyme structure 36 COX subunit gene structure and expression 37 COX activity regulation 39 Complex V (F 0 -Fi ATPase; ATP synthase) 40 Subunit composition, structure, and function 40 ATP synthase defects and related pathologies 44 Other enzymes bioenergetics 45 Adenine nucleotide translocator (ANT) 45 ANT structure 47 ANT regulation in the heart 47 ANT genes and their expression 47 ANT dysfunction plays a key role in cardiac pathology 48 Creatine kinase 49 Structure 50 Creatine kinase and the heart 51 PDH and the TCA (Krebs) cycle 52 Overall regulation of mitochondrial bioenergetic in the heart 53 Supply and demand, substrates, and oxygen and ATP-ADP levels 53 References 56

10 CONTENTS ix 3, Heart Mitochondrial Biogenesis 63 Overview 63 Introduction 63 Structure of mtdna 64 MtDNA Function 66 Replication 66 Regulation of mtdna replication 69 Mitochondrial transcription and RNA processing 70 Regulation of mitochondrial transcription and processing 72 Mitochondrial translation 73 Mitochondrial ribosomes 73 Initiation and elongation of translation 76 Mitochondria DNA repair 76 Nuclear participation in mitochondrial biogenesis 79 Nuclear regulatory proteins and coordination of transcriptional events 79 Hormones affecting both mitochondrial and nuclear transcription 82 Mitochondria import and assembly of proteins 83 Relevance of mitochondrial biogenesis 85 References ROS Generation, Antioxidants, and Cell Death 99 Overview 99 Introduction 99 The significance of ROS 100 Generation of ROS 100 Negative effect of ROS 102 Antioxidant defense 104 Role of ROS in cell signaling 106 ROS and cardiac pathology 106 ROS and apoptosis 108 Apoptosis and cell death 109 Myocardial apoptosis 112 References 113

11 Mitochondria and the Heart 5. Myocardial Ischemia and Cardioprotection 123 Overview 123 Introduction 123 Mitochondrial dysfunction in myocardial ischemia 124 Oxidation-phosphorylation decline in ischemia 124 Myocardial ischemia and oxidative stress 126 Myocardial ischemia and mitochondrial calcium flux 127 Gene expression 128 Reperfusion 129 Cardioprotection 129 Ischemic cardioprotection 129 Cascade of mitochondrial events in IPC 131 Signaling pathways 134 Adenosine and other ligands 134 Activation and translocation of PKC as a pivotal signaling event in the genesis of IPC and CP 136 Reactive oxygen species 137 Cardioprotection: An emerging field 138 Early and late IPC pathways 139 Potential applications to clinical medicine 142 References Mitochondria Dysfunction in Cardiomyopathy and Heart failure 157 Overview 157 Introduction 157 Mitochondria are the major source of bioenergy in the cardiac cell 158 What is the evidence for myocardial dependency on mitochondrial function? 160 Mitochondrial dysfunction and cardiomyopathy: Support from human studies 160

12 CONTENTS xi Clinical evidence of nuclear mutations in mitochondrial components 165 Constribution of transgenic models to the study of mitochondria in heart dysfunction 166 Evidence from animals models that mitochondrial bioenergetic enzymes play a critical role in HF 168 Mitochondrial dysfunction and other cellular pathways in cardiomyopathy 169 Mutations in contractile/sarcomere proteins and mitochondrial function 170 Mitochondrial function and cardiac hypertrophy 173 Calcium signaling and mitochondrial function in HF 174 Mitochondrial function and apoptosis in HF 174 What events occurring in HF are truly tissue-specific? 176 Future prospects 178 References Fatty Acid and Glucose Metabolism in Cardiac Disease 197 Overview 197 Introduction 197 Role of fatty acids and their metabolism in the normal cardiomyocyte: Structural and regulatory roles in cardiac cell membranes 198 Fatty acid transporters and glucose carriers 198 B ioenergetics of FAO 201 Cellular location of FAO and glucose oxidation 204 The effect of disorders of fatty acid and glucose metabolism on cardiac structure/function 205 Secondary effects on mitochondrial fatty acid (3-oxidation: Relationship to mitochondrial respiration and OXPHOS 208 Fatty acid metabolism defects and their association with cardiomyopathy and arrhythmias 208 Cardiomyopathy 208 Arrhythmias and conduction defects 209

13 xii Mitochondria and the Heart Fatty acids, glucose, and cardiac apoptosis 210 Abnormalities in mtdna and their association with both diabetes and cardiomyopathy 211 Molecular players in fatty acid-related cardiac diseases; modulation of gene expression 211 MCAD 211 VLCAD 212 CPT-II 212 MTP 212 PPAR 213 Peroxisome proliferator-activated receptor y coactivator (PGC- la) 215 Animal models of defective fatty acid metabolism and cardiac failure 216 Advances in diagnostics and treatment of fatty acid/cardiac disease 217 References Mitochondria in Pediatric Cardiology 229 Overview 229 MlTOCHONDRIAL CARDIOMYOPATHY 229 Introduction 229 Diagnosis 232 Clinical signs 233 Histological and electron microscopic (EM) analysis 233 Biochemical analysis 235 MtDNA analysis 236 Mitochondrial trna mutations 236 Mitochondrial structural gene mutations 241 ATP synthase (ATPase6) 241 Cytochrome b (cytb) 242 Mutations in COX and ND subunits 243 MtDNA depletion 244 MITOCHONDRIA AND CONGENITAL HEART DEFECTS (CHD) 245 Structural and functional cardiac defects 245 Cardiac arrhythmias 246

14 CONTENTS xiii Other congenital cardiomyopathies with mitochondrial defects 246 Congenital heart defects and mitochondrial respiration 247 Conclusions 248 References Mitochondria and the Aging Heart 263 Overview 263 Introduction 264 Bioenergetics and gene expression in the aging heart 265 Mitochondrial function and gene expression in the aging heart 266 ROS in the aging heart 268 Mitochondrial DNA damage in the aging heart 270 Rat model of cardiac aging: Defects in ETC 273 Gene expression 275 DNA copy number and damage analysis 275 Comments 276 On mitochondrial dysfunction 276 On mitochondrial DNA damage 277 On gene expression of mitochondrial stress proteins and cellular programming 277 On mitochondrial PT pore 278 Conclusions 278 Potential approaches to reverse mitochondrial dysfunction in the aging heart 279 References Heart Mitochondria Signaling Pathways 289 Overview 289 Introduction 289 Mitochondrial abnormalities, signaling defects, and myocardial disease 290

15 xiv Mitochondria and the Heart Mitochondrial signaling in myocardial ischemia and cardioprotection 291 Mitochondrial signaling and myocardial hypertrophy 294 Signaling the mitochondria: Key players 296 Nuclear gene activation 296 Protein kinases 298 Calcium signaling 300 Mitochondrial receptors 301 Signals of survival and stress impact heart mitochondria 302 Survival signals and apoptosis 304 Stress signals 306 Metabolic signals 307 Future prospects: Therapeutic targets and directions 307 The essential role played by mitochondriain in cytoprotective signaling and CP 307 Mitochondrial metabolic intermediates 308 Summary 309 References Treatment of Mitochondrial-Based Cardiac Diseases: Targeting the Organelle 323 Overview 323 Introduction 323 Treatment of respiratory and metabolic defects 324 Use of antioxidants 325 Treatment of FAO disorders, arrhythmias, and CHF 327 Cardioprotective agents 329 New approaches in treatment 333 Gene therapy in cardiovascular diseases 333 Mitochondria and gene therapy 336 Targeting mitochondria using nucleic acids 336 Targeting mitochondria using bioactive compounds 339 References 340