Mitochondria and the Heart
Buku ini diterbitkan tahun 2005 oleh Springer Science+Business Media, Inc, USA
adalah buku edisi Pertama.
Judul: Mitochondria and the Heart
Oleh: Jose Marin-Garcia, et al (Editor)
Penerbit: Springer Science+Business Media, Inc, USA
Tahun: 2005
Jumlah Halaman: 411 hal.
Editor:
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
Michael J Goldenthal
The Molecular Cardiology Institute,
Highland Park, New Jersey
Lingkup Pembahasan:
Buku ini mengemukakan Mitokondria paling penting dalam pengembangan dari beberapa ide penting dalam biologi modern. Sejak penemuan bahwa organel memiliki DNA sendiri dan mutasi tertentu yang ditemukan pada hubungannya dengan neuromuskuler dan penyakit kardiovaskular dan dengan
penuaan, sebuah extraordi-nary mengikuti jumlah publikasi, dan istilah obat mitokondria ini diciptakan. Selain itu, pemahaman tentang peran ganda yang mitokondria bermain di jantung homeostasis sel membuka pintu untuk eksperimen intensif untuk memahami patogenesis dan untuk menemukan pengobatan baru untuk penyakit kardiovaskular.
Selain perannya dalam generasi adenosin trifosfat, mitokondria merupakan regu-akhir jaringan kompleks interaksi seluler, yang melibatkan (1) generasi dan detoksifikasi spesies oksigen reaktif, termasuk anion superoksida, hy-Drogen peroksida, dan radikal hidroksil; (2) pemeliharaan glutathione antioksidan dalam keadaan berkurang dan tingkat yang memadai dari mitokondria matriks superoxide dismutase; (3) homeostasis kalsium sitoplasma, terutama di bawah kondisi pemuatan kalsium seluler; (4) transportasi metabolit antara sitoplasma dan matriks; (5) baik diprogram (apoptosis) dan nekrotik
kematian sel; dan (6) pertumbuhan sel dan pembangunan. Oleh karena itu tidak mengherankan bahwa organel ini telah datang untuk menjadi panggung di banyak penyelidikan saat ini penyakit kardiovaskular, penuaan, dan agingrelated penyakit. Seiring dengan kemajuan ini, upaya mengesankan cara pemahaman untuk pengembangan alat-alat baru dan metodologi untuk mempelajari struktur dan fungsi mitokondria, termasuk cara-cara ampuh untuk memvisualisasikan, memantau, dan mengubah fungsi organel untuk menilai genetik konsekuensi dari gangguan ini.
Daftar Isi:
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
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 (F0-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 bioenergetics in the heart 53
Supply and demand, substrates, and oxygen and ATP-ADP levels 53
References 56
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 85
4. 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
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 143
6. 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
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 179
7. 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
Bioenergetics 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
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 receptory coactivator (PGC- l a ) 215
Animal models of defective fatty acid metabolism and cardiac failure 216
Advances in diagnostics and treatment of fatty acid/cardiac disease 217
References 218
8. 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
Other congenital cardiomyopathies with mitochondrial defects 246
Congenital heart defects and mitochondrial respiration 247
Conclusions 248
References 249
9. 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 281
10. Heart Mitochondria Signaling Pathways 289
Overview 289
Introduction 289
Mitochondrial abnormalities, signaling defects, and myocardial disease 290
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 310
11. 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
12. Future Frontiers in Mitochondrial Cardiac Biology 351
Overview 351
Introduction 351
Disease gene identification: Diagnostic application 353
Modifying factors, Epigenetics, and SNPs 354
Animal models of mitochondrial-based heart disease 360
Cellular engineering 363
Applications of stem cells in mitochondrial defects and toxicology 365
References 367
Glossary 377
Index 388
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