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

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

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ISBN-13: 9781119017103
Publisher: Wiley
Publication date: 09/21/2015
Series: Wiley Series on Neuropharmacology
Sold by: Barnes & Noble
Format: NOOK Book
Pages: 448
File size: 12 MB
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About the Author

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.

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Table of Contents

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

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