Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection and Aging, Volume 4 - Mitophagy presents detailed information on the role of mitophagy, the selective autophagy of mitochondria, in health and disease, by delivering an in-depth treatment of the molecular mechanisms involved in mitophagy initiation and execution, as well as the role of mitophagy in Parkinson's Disease, cardiac aging, and skeletal muscle atrophy. The most current understanding of the proteins and pathways involved in mitophagy are covered, with specific attention to Nix and Bnip3, PINK1/Parkin, Atg32, and FUNDC1. The role of mitophagy in cancer, neurodegeneration, aging, infection, and inflammation is also discussed providing essential insights into the pathogenesis of a variety of mitochondria dysfunction-related diseases.
This book is an asset to newcomers as a concise overview of the current knowledge on mitophagy, while serving as an excellent update reference for more experienced scientists working on other aspects of autophagy. From these well-developed foundations, researchers, translational scientists, and practitioners may work to better implement more effective therapies against some of the most devastating human diseases.
• Brings together a wide swathe of experts (oncologists, neurosurgeons, physicians, research scientists, and pathologists) in the field of autophagy to discuss cutting-edge developments in this rapidly-advancing field
• Discusses in detail myriad aspects of yeast mitophagy, including proteins involved, generation of reactive oxygen species (ROS), and various mechanisms of mitochondrial quality control
• Builds upon recent advances in genome-scale approaches and computational tools to discuss the advances in regulation of autophagy at the systems level
• Organized for readers into easy-to-access sections: general applications; molecular mechanisms; and role in disease
Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection and Aging, Volume 4 - Mitophagy presents detailed information on the role of mitophagy, the selective autophagy of mitochondria, in health and disease, by delivering an in-depth treatment of the molecular mechanisms involved in mitophagy initiation and execution, as well as the role of mitophagy in Parkinson's Disease, cardiac aging, and skeletal muscle atrophy. The most current understanding of the proteins and pathways involved in mitophagy are covered, with specific attention to Nix and Bnip3, PINK1/Parkin, Atg32, and FUNDC1. The role of mitophagy in cancer, neurodegeneration, aging, infection, and inflammation is also discussed providing essential insights into the pathogenesis of a variety of mitochondria dysfunction-related diseases. This book is an asset to newcomers as a concise overview of the current knowledge on mitophagy, while serving as an excellent update reference for more experienced scientists working on other aspects of autophagy. From these well-developed foundations, researchers, translational scientists, and practitioners may work to better implement more effective therapies against some of the most devastating human diseases. Volumes in the Series
Front Cover 1
Autophagy 4
Copyright Page 5
Dedication 6
Mitophagy and Biogenesis 8
Contents 12
Foreword by Roberta A. Gottlieb 16
Foreword by Eeva-Liisa Eskelinen 18
Preface 20
Contributors 24
Abbreviations and Glossary 26
Autophagy: Volume 1 – Contributions 36
Autophagy: Volume 2 – Contributions 38
Autophagy: Volume 3 – Contributions 40
1 Introduction to Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, Volume 4 42
Introduction 43
Specific Functions of Autophagy (A Summary) 45
Autophagy in Normal Mammalian Cells 45
Major Types of Autophagies 46
Macroautophagy (Autophagy) 46
Microautophagy 47
Chaperone-Mediated Autophagy 47
Autophagosome Formation 48
Autophagic Lysosome Reformation 49
Autophagic Proteins 50
Protein Degradation Systems 51
Beclin 1 51
Non-Autophagic Functions of Autophagy-Related Proteins 51
Microtubule-Associated Protein Light Chain 3 52
Monitoring Autophagy 53
Reactive Oxygen Species (ROS) 54
Mammalian Target of Rapamycin (mTOR) 54
Role of Autophagy in Tumorigenesis and Cancer 55
Role of Autophagy in Immunity 57
Autophagy and Senescence 58
Role of Autophagy in Viral Defense and Replication 59
Role of Autophagy in Intracellular Bacterial Infection 60
Role of Autophagy in Heart Disease 61
Role of Autophagy in Neurodegenerative Diseases 62
Cross-Talk between Autophagy and Apoptosis 64
Autophagy and Ubiquitination 68
Aggresome: Ubiquitin Proteasome and Autophagy Systems 69
Autophagy and Necroptosis 69
Mitochondrial Fusion and Fission 70
Selective Autophagies 71
Allophagy 71
Glycophagy 72
Pexophagy 77
References 81
I: General Applications 88
2 Molecular Process and Physiological Significance of Mitophagy 90
Introduction 91
Selective Autophagy in Yeast 92
Selective Autophagy in Higher Eukaryotes 93
Mitochondrial Dysfunction in Age-Related Diseases 94
Mitochondrial Quality Control Systems 95
Mitophagy in Yeast 96
Mitophagy in Mammalian Cells 98
BNIP3L and BNIP3 98
FUNDC1 99
PARK2 and PINK1 99
Discussion and Perspectives 101
References 102
3 Principles of Mitophagy and Beyond 106
Introduction 106
Yeast Mitophagy 107
Principles and Mechanisms 107
The Importance of Mitophagy in Yeast 111
Mitophagy in Higher Eukaryotes 112
Fundc1 113
NIX and BNIP3 114
Pink1 (and Parkin) 116
General Conclusions 120
Acknowledgments 120
References 121
4 Quality Control in Mitochondria 126
Mechanisms of Mitochondrial Quality Control 127
Autophagy in S. cerevisiae 127
An Overview of Mitophagy in S. cerevisiae 127
Additional Mitochondrial Quality Control Mechanisms 129
Causes of Mitophagy 130
Yeast Proteins Involved in Mitophagy 131
ATG Proteins 131
MAP Kinases 132
Phosphatases 132
The RTG (Retrograde) Signaling Pathway and Mitophagy 133
Uth1 133
Functional Homologues of Yeast Mitophagy Proteins in Mammals 134
Mitochondrial Dynamics and Mitophagy 134
Future Directions of Yeast Mitophagy Research 137
References 137
5 Mitophagy: An Overview 144
Snapshot: Mitophagy 145
Molecular Mechanisms and Regulation 145
Mitochondrial Dynamics and Mitophagy 147
Monitoring Mitophagy 148
Physiological and Pathological Roles of Mitophagy 149
Development 149
Aging 150
Cancer 151
Neurodegenerative Diseases 151
Infection and Inflammation 153
Preventive Measures for Mitophagy-Related Diseases 154
Future Questions and Concluding Remarks 155
Acknowledgments 156
References 156
II: Molecular Mechanisms 158
6 Mitophagy Induction and Curcumin-Mediated Sonodynamic Chemotherapy 160
Introduction 160
Alternative Therapeutic Strategies: Ultrasound Therapy and Sonodynamic Chemotherapy 161
A Promising Sensitive Drug: Curcumin 162
Discussion 164
Acknowledgments 165
References 165
7 Role of Nix in the Maturation of Erythroid Cells through Mitochondrial Autophagy 168
Introduction 169
Nix and Mitochondrial Autophagy in Erythroid Differentiation 170
Expression of Nix during Terminal Erythroid Differentiation 170
Nix Regulates Mitochondrial Autophagy in Reticulocytes 170
Nix-Mediated Mitochondrial Clearance Involves Both Atg7-Dependent and Atg7-Independent Autophagy 171
Mechanisms of Nix-Mediated Mitochondrial Autophagy 172
Nix-Dependent Loss of Mitochondrial Membrane Potential in the Promotion of Mitochondrial Autophagy 172
Nix as a Mitochondrial Receptor for Binding to Autophagosome 174
Nix Domains Required for Mitochondrial Autophagy 175
Conclusions 176
Acknowledgments 176
References 176
8 Role of the Antioxidant Melatonin in Regulating Autophagy and Mitophagy 180
Introduction 181
Aging 183
Neurodegenerative Diseases 185
Cancer 186
Conclusions and Perspectives 188
References 189
9 Ubiquitin Ligase-Assisted Selective Autophagy of Mitochondria: Determining Its Biological Significance Using Droso ... 192
Introduction 193
Drosophila Models for Parkinson’s Disease 194
Mitophagy and Mitochondrial Dynamics 194
Muscle Degeneration Caused by Mitochondrial Defects 195
Mitophagy and Protein Translation Signaling 195
Crosstalk Between Mitophagy Signals and the Ubiquitin-Proteasome Pathway 196
Possible Roles of Mitophagy in Neurons 197
Regulators of Mitochondrial Maintenance Identified in Drosophila Studies 198
Tools for the Detection of Mitophagy in Drosophila 198
Concluding Remarks 200
References 200
10 Atg32 Confers Selective Mitochondrial Sequestration as a Cargo for Autophagy 204
Introduction 205
Atg32, a Mitophagy-Specific Protein 206
Genome-wide Screen for Mitophagy-Deficient Mutants in Yeast 206
Localization and Topology of Atg32 206
Atg32 Interacts with Atg11 for Selective MitochondriaL Degradation 207
Atg11, an Adaptor Protein for Selective Autophagy 207
Atg32 is a Receptor Protein for Mitophagy that Interacts with Atg11 208
Phosphorylation of Atg32 Mediates Atg32–Atg11 Interactions and Mitophagy 208
Atg32 Interacts with Atg8 208
Induction and Regulation of Mitophagy 209
Mitophagy Induction in Yeast 209
Signaling Pathways that Regulate Mitophagy 210
Other Factors Related to Mitophagy in Yeast 210
Physiological Role of Mitophagy in Yeast 211
Acknowledgments 212
References 213
11 PARK2 Induces Autophagy Removal of Impaired Mitochondria via Ubiquitination 216
Introduction 217
Mitochondrial Dysfunction and Parkinson’s Disease 218
Park2/Parkin and Intracellular Quality Control 219
Relevance of Parkin-Mediated Mitophagy to Parkinson’s Disease Pathogenesis 225
Concluding Remarks 227
Acknowledgments 227
References 228
12 Ubiquitination of Mitofusins in PINK1/Parkin-Mediated Mitophagy 230
Introduction 231
Mitochondrial Dynamics 231
PINK1/Parkin-Mediated Mitophagy 233
Ubiquitination of Mfn1 and Mfn2 by Parkin 235
Consequences of Mfn Ubiquitination 236
Conclusions and Perspectives 238
Acknowledgments 239
References 239
13 Mitochondrial Alterations and Mitophagy in Response to 6-Hydroxydopamine 242
Introduction 243
Mitochondrial Alterations 243
Biochemical Mitochondrial Alterations 243
Morphological Mitochondrial Alterations 244
6-OHDA and Mitochondrial Dynamics 245
6-OHDA and Autophagy 246
Acknowledgments 249
References 249
III: Role in Disease 252
14 Role of Mitochondrial Fission and Mitophagy in Parkinson’s Disease 254
Introduction 255
Mitochondrial Fission and PD 255
Mitophagy 256
Genetic Factors 258
a-Synuclein 258
Leucine-Rich Repeat Kinase 2 260
DJ-1 261
Parkin 261
PTEN-Induced Kinase 1 262
Omi/HtrA2 263
Sporadic PD 263
References 265
15 Mitophagy Controlled by the PINK1-Parkin Pathway Is Associated with Parkinson’s Disease Pathogenesis 268
Introduction 269
Parkin has Ubiquitin Ligase Activity 269
Genetic Association Between the PD Genes PARKIN and PINK1 270
Pink1 and Parkin are Involved in the Regulation of Mitochondrial Dynamics 270
Parkin is Involved in the Elimination of Damaged Mitochondria Through the Mitophagy Pathway 271
PINK1 Regulates the Mitochondrial Translocation of Parkin 271
Molecular Regulation of PINK1 and Parkin 273
PINK1 and Parkin Regulate Mitochondrial Motility 275
Physiological and Pathological Roles of Mitophagy by the PINK1-Parkin Pathway 276
Discussion 277
Acknowledgments 277
References 277
16 Loss of Mitochondria during Skeletal Muscle Atrophy 280
Introduction 281
Ubiquitin-Proteasome System Mediated Muscle Atrophy 283
Autophagy-Lysosomal System Mediated Muscle Atrophy 285
Mitophagy-Mediated Muscle Atrophy 287
Mechanisms Underlying the Loss of Mitochondria During Muscle Atrophy 289
Conclusion and Future Directions 290
References 291
17 Role of Impaired Mitochondrial Autophagy in Cardiac Aging 294
Introduction 295
Mechanisms and Consequences of Mitochondrial Dysfunction in the Aging Heart 296
Mitochondria as a Source of Oxidants 296
Mechanisms of Mitochondrial Dysfunction in the Aging Heart 296
Consequences of Mitochondrial Dysfunction on Heart Physiology 298
Contribution of Impaired Mitochondrial Quality Control to Cardiac Aging 300
Role of Altered Mitochondrial Dynamics in Cardiac Aging 300
Contribution of Altered Mitochondrial Autophagy to Heart Senescence 301
Mitochondrial Dysfunction and Quality Control: Novel Pharmacological Targets Against Cardiac Aging and Cardiovascular Disea ... 303
Conclusion 304
References 305
Index 308
Preface
M.A. Hayat
This is the fourth volume of the series discussing almost all aspects of the autophagy machinery. This volume presents detailed information on the role of mitophagy in health and disease. The most important function of mitochondria is to supply a large amount of energy required for normal cellular activities. This organelle is also involved in a large number of other essential cellular functions, including thermogenesis, iron-sulfur cluster biogenesis, biosynthesis of heme and certain lipids and amino acids, autophagy, apoptosis, immune response, cell death, cellular homeostasis and metabolism, differentiation, aging, and the production of reactive oxygen species (ROS). Therefore, the maintenance of a healthy pool of mitochondria is vital for normal cellular physiology and survival. On the other hand, mitochondrial dysfunction can have severe consequences including aging and pathogenesis of neurodegenerative diseases. In this respect, Parkinson’s disease, skeletal muscle atrophy, and cardiovascular disease are discussed here. Various steps involved in mitophagy are detailed, and molecular mechanisms underlying this autophagic machinery are reviewed both in yeast and metazoa. Inclusion of information on autophagy including mitophagy in yeast in this volume is relevant and important because studies of yeast have clarified the fundamental principles of autophagy, which serve as a guide for studies of autophagy in metazoans. Almost all aspects of yeast mitophagy, including proteins involved, generation of reactive oxygen species (ROS), and various mechanisms of mitochondrial quality control, are discussed in detail.
As mentioned above, maintaining a healthy and functional population of mitochondria is critically important for all eukaryotic cells. Several quality control systems exist within mitochondria, and an important link between mitochondria maintenance and macroautophagy (mitophagy) has been established. Mitophagy is one of the primary mechanisms for mitochondrial quality control and serves to selectively eliminate dysfunctional or excess mitochondria via an autophagic process that is tightly regulated. The failure to maintain adequate mitophagy leads to accumulation of dysfunctional mitochondria within cells, resulting in cellular dysfunction. Diseases associated with impaired mitophagy include neurodegenerative diseases, myopathies, obesity, and diabetes, most of which are discussed in this volume. The recent advances in our understanding of mitophagy will provide essential insights into the pathogenesis of a variety of mitochondria dysfunction-related diseases.
Several reviews presenting the current understanding of the molecular mechanisms of autophagy involved in cancer, neurodegeneration, aging, infection, and inflammation are included in this volume. At the molecular level, a large group of proteins has been identified in various model organisms which mediate the association of damaged or dysfunctional mitochondria with the autophagic machinery. Four mammalian mitochondrial proteins (tags) (Nix, PINK1, Bnip3, and FUNDC1) are discussed; also the role of Atg32 protein in yeast is explained. PINK1 (encoded by the PARK6 gene) and Parkin (encoded by the PARK2 gene) proteins have provided the most important insight into the mechanism of autophagy in mammalian cells.
PINK1/Parkin mutants (Drosophila) show severe developmental abnormalities associated with mitochondrial dysfunction. In humans, mutations of PINK1 or Parkin are responsible for most cases of early-onset Parkinson’s disease. In healthy mitochondria, PINK1 is imported into mitochondrial inner membrane where it is subsequently degraded by PARL, but in mitochondria with disrupted membrane potential, it is retained on the mitochondrial outer membrane where it recruits Parkin from the cytosol. Once recruited, Parkin initiates mitophagy to eliminate dysfunctional mitochondria. The molecular events involved in PINK1/Parkin promotion of mitophagy are detailed in two chapters.
The role of transmembrane protein Atg32 in autophagy is explained in this volume. Phosphorylated Atg32 is an important mitochondrial tag located in the mitochondrial outer membrane. Phosphorylation of Atg32 is required for recruiting the scaffold protein Atg11, resulting in targeting mitochondria for degradation. Independent of Atg11 binding, Atg8 is recruited to Atg32. Atg8 is essential for autophagosome assembly. Atg11 is also required for other types of autophagies. In fact, the formation of a tripartite (Atg32/Atg11/Atg8) initiator complex is common. Casein kinase 2 is essential for the activation of Atg32.
Another example discussed in this volume is the critical role of Nix and related Bnip3 in mitochondrial autophagy. Nix is located in the mitochondrial outer membrane. The transmembrane domain, but not the BH3 domain of Nix, is essential for its activity. Nix is not required for autophagosome formation, but is essential for sequestration of mitochondria into autophagosomes. Nix plays a vital role in the maturation of the reticulocyte to erythrocyte, during which mitochondria are eliminated by mitophagy.
FUNDC1 is a less known protein located in the mitochondrial outer membrane, with structural similarity to Atg32. Hypoxia induces FUNDC1-dependent mitophagy. Mitochondrial fragmentation accompanies FUNDC1-dependent mitophagy. The role of FUNDC1-dependent mitophagy in hypoxic cancer cells is discussed here.
An interesting example of the role of mitophagy is in mammalian reproduction. Mitophagy occurs physiologically during the removal of sperm mitochondria from egg cells upon fertilization; this process is called allophagy. One possible explanation for such selective mitophagy is that paternal mitochondria are heavily damaged by ROS prior to fertilization, and need to be removed to prevent potentially deleterious effects in the next generation.
It is known that the relentless loss of dopaminergic neurons in the midbrain causes Parkinson’s disease. Mitochondrial and lysosomal functions decrease with age and, therefore, both are implicated in aging and age-related disorders such as Parkinson’s disease. That impaired mitochondrial function is a predominant feature of this disease is explained in this volume. Two specific processes, mitochondrial fission and mitophagy, involved in this disease are described; the former occurs as an early step during neurodegeneration.
As indicated previously, two Parkinson’s disease-associated genes, PINK1 and Parkin, are involved in the maintenance of healthy mitochondria. The pivotal role played by Parkin in maintaining dopaminergic neuronal survival is underscored here, and its dysfunction represents a cause of Parkinson’s disease. Parkin in cooperation with PINK1 specifically recognizes damaged mitochondria, isolates them from the mitochondrial network, and eliminates them through the ubiquitin-proteasome and mitophagy pathways. It is emphasized that PINK1 and Parkin protein identify and segregate damaged mitochondria for degradation by mitophagy via ubiquitination of several mitochondrial proteins including mitofusins. Mutations of PARK2 gene (encoding the ubiquitin ligase Parkin) cause not only familial parkinsonism but also a sporadic form of this disease. As stated before, Parkin is a key regulator of mitochondrial quality control. However, presently the model of Parkin-mediated mitophagy is being debated, which is updated in this volume. The understanding of the molecular mechanisms of PINK1 and Parkin-mediated mitochondrial regulation is also reviewed here.
Intrinsic aging of the cardiovascular system, in addition to chronic exposure to cardiovascular risk factors, is inevitable. This results in the development of cardiovascular disease later in life. It is pointed out that the impairment in mitochondrial function arising from failure of mitochondrial quality control is a major contributing factor to heart senescence. It is also pointed out that damaged mitochondria produce increased amounts of ROS, resulting in oxidative damage to cardiomyocyte components.
Loss of muscle mass and function results mostly from accelerated protein degradation by the ubiquitin-proteasome system and autophagy-lysosome systems. The signaling mechanism underlying the increased protein degradation during muscle atrophy from a genetic perspective is explained here. The importance of mitophagy during skeletal muscle atrophy is pointed out.
The text is divided into three subheadings (General Applications, Molecular Mechanisms, and Role in Disease) for the convenience of the readers.
By bringing together a large number of experts (oncologists, physicians, medical research scientists, and pathologists) in the field of mitophagy, it is my hope that substantial progress will be made against terrible diseases afflicting humans. It is difficult for a single author to discuss effectively and comprehensively various aspects of an exceedingly complex process such as mitophagy. Another advantage of involving more than one author is to present different points of view on various controversial aspects of the role of mitophagy in health and disease. I hope these goals will be fulfilled in this and future volumes of this series.
This volume was written by 39 contributors representing 9 countries. I am grateful to them for their promptness in accepting my suggestions. Their practical experience highlights the very high quality of their writings, which should build and further the endeavors of the readers in this important medical field. I respect and appreciate the hard work and exceptional insight into the mitophagy machinery provided by these contributors.
It is my hope that subsequent...
Erscheint lt. Verlag | 28.7.2014 |
---|---|
Sprache | englisch |
Themenwelt | Sachbuch/Ratgeber ► Gesundheit / Leben / Psychologie |
Medizin / Pharmazie ► Medizinische Fachgebiete ► Dermatologie | |
Studium ► 1. Studienabschnitt (Vorklinik) ► Histologie / Embryologie | |
Studium ► 2. Studienabschnitt (Klinik) ► Pathologie | |
Studium ► Querschnittsbereiche ► Infektiologie / Immunologie | |
Naturwissenschaften ► Biologie ► Zellbiologie | |
ISBN-10 | 0-12-405533-8 / 0124055338 |
ISBN-13 | 978-0-12-405533-9 / 9780124055339 |
Haben Sie eine Frage zum Produkt? |
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