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The Functions, Disease-Related Dysfunctions, and Therapeutic Targeting of Neuronal Mitochondria

Wiley Series on Neuropharmacology 1. Aufl.

von: Valentin K. Gribkoff, Elizabeth A. Jonas, J. Marie Hardwick
171,99 €
Verlag:	Wiley
Format:	PDF
Veröffentl.:	25.09.2015
ISBN/EAN:	9781119016724
Sprache:	englisch
Anzahl Seiten:	448

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Titelbeschreibung

This book presents advances in the field of neuronal mitochondria – functions, relation to therapeutics, and pharmacology. For scientists and researchers in both industry and academia, this book provides detailed discussion, examples, and approaches, to illustrate the potential of mitochondria as therapeutic targets for neuronal diseases. • Helps readers understand the regulation of mitochondrial cellular processes, such as substrate metabolism, energy production, and programmed versus sporadic cell death • Offers insights on the development of strategies for targeted therapeutic approaches and potential personalized treatments • Includes examples of mitochondrial drugs, development, and mitochondria-targeted approaches for more efficient treatment methods and further developments in the field • Covers the model systems and approaches needed for the development of new drugs for the central nervous system to provide potential modern therapeutics for neurodegenerative disorders

Inhaltsverzeichnis

Contributors xiv Preface xviii Section I Mitochondrial Structure and Ion Channels 1 1 Mitochondrial Permeability Transition: A Look From a Different Angle 3 Nickolay Brustovetsky 1.1 Regulation of Intracellular Calcium in Neurons 3 1.2 Calcium Overload and Mitochondrial Permeability Transition 4 1.3 The Mitochondrial Transition Pore 8 1.3.1 Evidence for ANT and VDAC as Components of the PTP 8 1.3.2 Alternative Hypotheses of mPTP Composition 17 Acknowledgments 22 References 22 2 The Mitochondrial Permeability Transition Pore, the c?]Subunit of the F1FO AT P Synthase, Cellular Development, and Synaptic Efficiency 31 Elizabeth A. Jonas, George A. Porter, Jr., Gisela Beutner, Nelli Mnatsakanyan and Kambiz N. Alavian 2.1 Introduction 32 2.2 Mitochondria at the Center of Cell Metabolism and Cell Death 32 2.3 Mitochondrial Inner Membrane Leak: Regulator of Metabolic Rate and Uncoupling 32 2.4 Mitochondrial Inner Membrane Channels and Exchangers are Necessary for Ca2+ Cycling and Cellular Ca2+ Dynamics 33 2.5 Mitochondrial Inner and Outer Membrane Channel Activity Regulates Ca2+ Re?]Release from Mitochondria after Buffering 34 2.6 Bcl?]2 Family Proteins Regulate Pathological Outer Mitochondrial Membrane Permeabilization (MOMP) 35 2.7 Pathological Inner Membrane Depolarization: Mitochondrial Permeability Transition 36 2.8 The Quest for an Inner Membrane Ca2+?]Sensitive Uncoupling Channel: The PT Pore 37 2.8.1 Electrophysiologic Properties of the mPTP 37 2.8.2 Characterization of a Molecular Complex Regulating the Pore 39 2.8.3 Bcl?]xL Regulates Metabolic Efficiency by Binding to the β?]Subunit of the ATP Synthase 39 2.8.4 CypD Binds to ATP Synthase and Regulates Permeability Transition 40 2.8.5 PT Activity Regulates Cardiac Development 41 2.8.6 Regulatory Molecules Do Not Form the Pore of mPTP 42 2.9 The mPTP: A Molecular Definition 43 2.9.1 The c?]Subunit of F1FO ATP Synthase Comprises the PT Pore 43 2.9.2 The c?]Subunit of ATP Synthase Creates the High Conductance mPTP Pore 45 2.9.3 F1 Regulates Biophysical Characteristics of the Purified c?]Subunit 45 2.9.4 Structural Location of the Pore within the c?]Subunit Ring 48 2.10 Closing of the mPTP May Enhance Mitochondrial Metabolic Plasticity and Regulate Synaptic Properties in Hippocampal Neurons 49 2.11 mPTP Opening Correlates with Cell Death in Acute Ischemia, ROS Damage, or Glutamate Excitotoxicity 49 2.12 Pro?]Apoptotic Proteolytic Cleavage Fragment of Bcl?]xL Causes Large Conductance Mitochondrial Ion Channel Activity Correlated with Hypoxic Synaptic Failure: Outer Mitochondrial Channel Membrane Activity Alone or mPTP? 51 2.13 S ynaptic Responses Decline during Long?]Term Depression in Association with Bcl?]2 Family?]Regulated Mitochondrial Channel Activity 52 2.14 S ynapse Loss During Neurodegenerative Disease May Require Mitochondrial Channel Activity 53 2.15 Conclusions 54 Acknowledgments 55 References 55 3 Mitochondrial Channels in Neurodegeneration 65 Pablo M. Peixoto, Kathleen W. Kinnally and Evgeny Pavlov 3.1 Introduction 65 3.2 Mitochondrial Channels in the Healthy Neuron 66 3.2.1 Voltage Dependent Anion?]Selective Channel is the Food Channel 66 3.2.2 Protein Import Channels 67 3.2.3 Mitochondrial Ca2+ Channels 74 3.2.4 Mrs2 – Mg2+ Channel 75 3.2.5 Mitochondrial K+ Channels 76 3.2.6 Mitochondrial Centum Pico?]Siemens 76 3.2.7 Alkaline?]Induced Anion?]Selective Activity and Alkaline?]Induced Anion?]Selective Activity 77 3.2.8 Chloride Intracellular Channels 78 3.2.9 Alternative Ion Transport Pathways 78 3.3 Mitochondrial Channels in the Dying Cell 79 3.3.1 Apoptosis 79 3.3.2 Necrosis 80 3.4 Mitochondrial Channels in Neurodegenerative Diseases 83 3.5 Conclusions 87 References 87 Section II Control of Mitochondrial Signaling Networks 101 4 Mitochondrial Ca2+ Transport in the Control of Neuronal Functions: Molecular and Cellular Mechanisms 103 Yuriy M. Usachev 4.1 Introduction 103 4.2 Physiological and Pharmacological Characteristics of Mitochondrial Ca2+ Transport in Neurons 106 4.3 Molecular Components of Mitochondrial Ca2+ Transport in Neurons 110 4.4 Mitochondrial Ca2+ Signaling and Neuronal Excitability 114 4.5 Mitochondrial Ca2+ Cycling in the Regulation of Synaptic Transmission 115 4.6 Mitochondrial Ca2+ Transport and the Regulation of Gene Expression in Neurons 118 4.7 Future Directions 119 Acknowledgments 120 References 120 5 A MP?]Activated Protein Kinase (AMPK) as a Cellular Energy Sensor and Therapeutic Target for Neuroprotection 130 Petronela Weisová, Shona Pfeiffer and Jochen H. M. Prehn 5.1 Introduction 130 5.1.1 AMPK Expression, Structure, and Activity Regulation in Brain 131 5.1.2 Other Roles for AMPK 135 5.1.3 AMPK in Neurological Diseases and Neurodegeneration 137 5.2 Conclusion and Future Perspectives 139 References 139 6 HDA C6: A Molecule with Multiple Functions in Neurodegenerative Diseases 146 Yan Yan and Renjie Jiao 6.1 Introduction 146 6.2 Molecular Properties of HDAC6 147 6.2.1 Classes of the HDAC Family 147 6.2.2 HDAC6 149 6.3 HDAC6 and Neurodegenerative Diseases 151 6.3.1 HDAC6 and Elimination of Proteotoxicity in Neurodegenerative Diseases 152 6.3.2 HDAC6 and Autophagic Clearance of Dysfunctional Mitochondria 156 6.4 Perspectives 158 References 159 7 Neuronal Mitochondrial Transport 166 Adam L. Knight, Yanmin Chen, Tao Sun and Zu?]Hang Sheng 7.1 Introduction 166 7.2 Complex Motility Patterns of Axonal Mitochondria 168 7.3 Mechanisms of Mitochondrial Transport 169 7.3.1 Kinesin Motors and Anterograde Transport 169 7.3.2 Dynein Motors and Retrograde Transport 171 7.3.3 Interplay of Opposing Motor Proteins 172 7.4 Mechanisms of Axonal Mitochondrial Anchoring 172 7.5 Regulation of Mitochondrial Transport by Synaptic Activity 173 7.6 Mitochondrial Transport and Synaptic Transmission 174 7.7 Mitochondrial Transport and Presynaptic Variability 175 7.8 Mitochondrial Transport and Axonal Branching 176 7.9 Mitochondrial Transport and Mitophagy 178 7.10 Conclusions and New Challenges 180 Acknowledgments 180 References 181 8 Mitochondria in Control of Hypothalamic Metabolic Circuits 186 Carole M. Nasrallah and Tamas L. Horvath 8.1 Introduction 186 8.2 Yin?]Yang Relationship between Components of Hypothalamic Feeding and Satiety Circuits 187 8.3 Mitochondria and Their Dynamics 189 8.4 Metabolic Principles of Hunger and Satiety Promotion: Mitochondria in Support of Fat Versus Glucose Utilization 191 8.5 Mitochondria Dynamics and Cellular Energetics 193 8.5.1 Fission and Fusion of Mitochondria in Hypothalamic Feeding Circuits 194 8.6 Mitochondrial Dysfunction and Metabolic Disorders 196 8.7 Conclusions 197 References 197 9 Mitochondria Anchored at the Synapse 203 George A. Spirou, Dakota Jackson and Guy A. Perkins 9.1 Introduction 203 9.2 Calibrated Positioning of Mitochondria 204 9.3 Mitochondria and Crista Structure 206 9.4 Adhering Junctions and Linkages to the Cytoskeleton 208 9.5 Linkages of the OMM to the Mitochondrial Plaque and Reticulated Membrane 210 9.6 Functions of the Organelle Complex 211 9.7 MACs and Filamentous Contacts: A Continuum of Structure? 213 Acknowledgments 214 References 214 Section III Defective Mitochondrial Dynamics and Mitophagy 219 10 Neuronal Mitochondria are Different: Relevance to Neurodegenerative Disease 221 Sarah B. Berman and J. Marie Hardwick 10.1 Introduction 221 10.2 Mitochondrial Dynamics in Neurons and Neurodegenerative Disease 222 10.2.1 Quantifying Mitochondrial Dynamics 222 10.2.2 Mutations and Toxins Alter Mitochondrial Dynamics in Neurological Disease 223 10.3 Triggering Mitophagy in Neurons versus Other Cell Types 226 10.3.1 Parkin Mitophagy Pathway Disease Genes 226 10.3.2 Metabolic States of Neurons Modulate Mitophagy Induction 227 10.3.3 Neurons Distinguish between Different Types of Mitochondrial Damage 228 10.4 BCL?]xL: The Guardian of Mitochondria 231 10.4.1 BCL?]xL Regulates Mitochondrial Dynamics and Neuronal Activity 231 10.4.2 BCL?]xL Regulates Mitochondrial Energetics 232 Acknowledgments 233 References 233 11 PINK1 as a Sensor for Mitochondrial Function: Dual Roles 240 Erin Steer, Michelle Dail and Charleen T. Chu 11.1 Introduction 240 11.2 PINK1 Promotes Mitochondrial Function 241 11.3 Healthy Mitochondria Import and Process PINK1 244 11.3.1 Localization and Processing of PINK1 Depends on an Intact ΔΨm 244 11.4 Accumulation of Full Length?]PINK1 as a Sensor of Mitochondrial Dysfunction 245 11.5 Cytosolic PINK1 as a Sensor for Mitochondrial Function 247 11.5.1 Cytosolic PINK1 Suppresses Cell Death and Autophagy/Mitophagy 247 11.5.2 Cytosolic PINK1 Promotes Neurite Extension and Cell Survival 248 11.6 PINK1 and Mitochondrial Dynamics 248 11.7 Dual Roles for PINK1 as a Sensor of Mitochondrial Function and Dysfunction 249 References 249 12 A Get?]Together to Tear It Apart: The Mitochondrion Meets the Cellular Turnover Machinery 254 Gian?]Luca McLelland and Edward A. Fon 12.1 Mitochondrial Quality Control in Neurodegeneration 254 12.2 An Overview of the Ubiquitin?]Proteasome System 255 12.3 Activities of the Cytosolic Proteasome at the Outer Mitochondrial Membrane 256 12.4 The Turnover of Whole Mitochondria by Mitophagy 260 12.5 Proteasomes and Phagophores Converge in the PINK1/parkin Pathway 261 12.6 Implications of PINK1?]/Parkin?]Dependent Mitophagy in the Brain and in PD 265 12.7 Emerging Mitochondrial Quality Control Mechanisms 267 References 268 13 Mitochondrial Involvement in Neurodegenerative Dementia 280 Laura Bonanni, Valerio Frazzini, Astrid Thomas and Marco Onofrj 13.1 Introduction 280 13.2 Mitochondrial Dysfunction in Alzheimer Disease 281 13.3 Mitochondrial Dysfunction, Bioenergetic Deficits, and Oxidative Stress in AD 282 13.4 Mitochondrial Fragmentation in AD 283 13.5 S ynaptic Mitochondria in AD 283 13.6 Mitochondrial Dysfunction and Cationic Dyshomeostasis in AD 284 13.7 Mitochondrial Dysfunction in DLB 286 13.8 LRRK2 Mutations, Mitochondria and DLB 287 13.9 Akinetic Crisis in Synucleinopathies is Linked to Genetic Mutations Involving Mitochondrial Proteins 287 13.10 Conclusions 289 References 289 Section IV Mitochondria-Targeted Therapeutics and Model Systems 295 14 Neuronal Mitochondria as a Target for the Discovery and Development of New Therapeutics 297 Valentin K. Gribkoff 14.1 Neurodegenerative Disorders and the Status of Drug Discovery 297 14.2 Mitochondria as Targets for the Development of New NDD Therapies 300 14.3 The Effects of Dexpramipexole on Mitochondrial Conductances: An Example of an Approach for ALS and Other NDDs 301 14.3.1 ALS as a Therapeutic Target 301 14.3.2 Mitochondrial Dysfunction in ALS 303 14.3.3 Dexpramipexole and Bioenergetic Efficiency: Preclinical Studies 303 14.3.4 Dexpramipexole in the Clinic 309 14.4 What is the Future of a Mitochondrial Approach for NDD Therapy? 313 Acknowledgments 314 References 315 15 Mitochondria as a Therapeutic Target for Alzheimer’s Disease 322 Clara Hiu?]Ling Hung, Sally Shuk?]Yee Cheng, Simon Ming?]Yuen Lee and Raymond Chuen?]Chung Chang 15.1 Introduction 322 15.2 Mitochondrial Abnormalities and Dysfunction in Alzheimer’s Disease 323 15.2.1 Mitochondrial Morphology and Ultrastructure 323 15.2.2 Beta Amyloid, Tau, and Mitochondria 323 15.2.3 Defective Mitochondria at Synapses 325 15.2.4 Impaired Mitochondrial Dynamics 325 15.2.5 Oxidative Stress 326 15.2.6 Ca2+ Dysregulation in Mitochondria 326 15.2.7 Mitochondrial Permeability Transition Pore 327 15.3 Mitochondria as a Drug Target 327 15.3.1 Targeting Drugs to Mitochondria 327 15.3.2 Mitochondria?]Targeted Antioxidants 329 15.3.3 Mitochondrial Ca2+ Pathways 330 15.3.4 Mitochondrial Permeability Transition Pore 331 15.3.5 Mitochondrial Dynamics 331 15.3.6 Mitochondrial Metabolism 332 15.3.7 Mitochondrial Biogenesis 332 15.3.8 Limitations of Mitochondrial?]Targeted Drugs 333 15.4 Conclusions 333 Acknowledgments 333 References 334 16 Mitochondria in Parkinson’s Disease 339 Giuseppe Arena and Enza Maria Valente 16.1 Introduction 339 16.2 Role of Mitochondria in Sporadic PD 340 16.2.1 Complex I Deficiency and mtDNA Defects 340 16.2.2 Oxidative Stress and ROS Production 341 16.3 Mitochondrial Dysfunction in Monogenic PD 342 16.3.1 Autosomal Dominant PD 343 16.3.2 Autosomal Recessive PD 346 16.4 Conclusions 350 References 351 17 Therapeutic Targeting of Neuronal Mitochondria in Brain Injury 359 Heather M. Yonutas, Edward D. Hall and Patrick G. Sullivan 17.1 Introduction 359 17.2 Mitochondria Bioenergetics 360 17.3 Traumatic Brain Injury 363 17.3.1 Models of TBI 364 17.3.2 Secondary Injury Cascade of TBI 366 17.4 Pharmaceutical Interventions 370 17.4.1 Targeting Mitochondrial Dysfunction 370 17.4.2 Targeting Oxidative Stress 371 17.4.3 Interventions with Multiple Targets 372 17.5 Conclusion 372 References 373 18 The Use of Fibroblasts from Patients with Inherited Mitochondrial Disorders for Pathomechanistic Studies and Evaluation of Therapies 378 Devorah Soiferman and Ann Saada 18.1 Introduction 378 18.1.1 Identification of Mitochondrial Disorders 380 18.1.2 Pathomechanism of Mitochondrial Disorders 381 18.1.3 Treatment of Mitochondrial Disorders 382 18.1.4 Models of Mitochondrial Disorders 383 18.2 Pathomechanistic Studies of Mitochondrial Disorders in Patients’ Fibroblasts 385 18.2.1 Reduced Cellular ATP 385 18.2.2 Increased Oxidative Stress 386 18.2.3 Reduction of Mitochondrial Membrane Potential 386 18.2.4 Disruption of Calcium Homeostasis 386 18.2.5 Coenzyme Q10 Deficiency 387 18.2.6 Mitochondrial Dynamics and Mitophagy 387 18.3 Evaluation of Therapeutic Options Using Patient Derived Fibroblasts 388 18.3.1 Pharmacological Approaches 388 18.3.2 Genetic Manipulation 391 18.4 Conclusion 392 Acknowledgments 393 References 393 Index 399

Autorenportrait

Valentin Gribkoff is an Associate Professor Adjunct in the Department of Internal Medicine at Yale University School of Medicine and is a founding member of The Northwoods Group, a biotech consulting and development consortium. He previously co-edited Structure, Function and Modulation of Neuronal Voltage-Gated Ion Channels (Wiley, 2009) and is a co-editor of the Wiley Series on Neuropharmacology. Elizabeth Jonas is an Associate Professor at the Departments of Internal Medicine, Section of Endocrinology, and Neurobiology at Yale University School of Medicine. J. Marie Hardwick is the David Bodian Professor of Molecular Microbiology and Immunology at The Johns Hopkins Bloomberg School of Public Health.

Back cover copy

The powerhouses of cells, mitochondria are responsible for generating energy, regulation of cellular homeostasis and and are involved in cell death-signaling pathways. A wide range of neurological disorders – such as Alzheimer’s, Parkinson’s, schizophrenia, bipolar disease, migraines, and strokes – have all been traced back to the accumulation of mitochondrial DNA (mtDNA) damage or mitochondrial dysfunction. Focusing on neuronal mitochondria, this book discusses their functions and properties, and the relation of dysfunctional mitochondria to neuronal disease, and to the future development of new therapies. For scientists and researchers in both industry and academia, the expert contributors provide detailed discussions, examples, and approaches to illustrate the potential of mitochondria as therapeutic targets for neuronal diseases – like Alzheimer’s, Parkinson’s, strokes, and brain trauma. Together, these chapters offer the tools and perspectives to help decipher challenges and develop strategies for more targeted therapeutic approaches and, potentially, for personalized treatments. Using recent evidence and examples of drugs, targeted approaches, and an in-depth understanding of cell death; this book: • Presents up-to-date information and advances in the field of neuronal mitochondria, including the promise of future therapeutics • Helps readers understand the regulation of mitochondrial cellular processes, such as substrate metabolism, energy production, and programmed verses sporadic cell death • Includes examples of mitochondrial drugs, development, and mitochondria-targeted approaches for more efficient treatment methods and further developments in the field • Covers the development of existing and emerging therapeutic approaches for neuronal disorders that may in the future become critical components of modern therapeutics