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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• Contributors xivPreface xviiiSection I Mitochondrial Structure and Ion Channels 11 Mitochondrial Permeability Transition: A Look From a Different Angle 3Nickolay Brustovetsky1.1 Regulation of Intracellular Calcium in Neurons 31.2 Calcium Overload and Mitochondrial Permeability Transition 41.3 The Mitochondrial Transition Pore 81.3.1 Evidence for ANT and VDAC as Components of the PTP 81.3.2 Alternative Hypotheses of mPTP Composition 17Acknowledgments 22References 222 The Mitochondrial Permeability Transition Pore, the c]Subunit of the F1FO AT P Synthase, Cellular Development, and Synaptic Efficiency 31Elizabeth A. Jonas, George A. Porter, Jr., Gisela Beutner, Nelli Mnatsakanyan and Kambiz N. Alavian2.1 Introduction 322.2 Mitochondria at the Center of Cell Metabolism and Cell Death 322.3 Mitochondrial Inner Membrane Leak: Regulator of Metabolic Rate and Uncoupling 322.4 Mitochondrial Inner Membrane Channels and Exchangers are Necessary for Ca2+ Cycling and Cellular Ca2+ Dynamics 332.5 Mitochondrial Inner and Outer Membrane Channel Activity Regulates Ca2+ Re]Release from Mitochondria after Buffering 342.6 Bcl]2 Family Proteins Regulate Pathological Outer Mitochondrial Membrane Permeabilization (MOMP) 352.7 Pathological Inner Membrane Depolarization: Mitochondrial Permeability Transition 362.8 The Quest for an Inner Membrane Ca2+]Sensitive Uncoupling Channel: The PT Pore 372.8.1 Electrophysiologic Properties of the mPTP 372.8.2 Characterization of a Molecular Complex Regulating the Pore 392.8.3 Bcl]xL Regulates Metabolic Efficiency by Binding to the β]Subunit of the ATP Synthase 392.8.4 CypD Binds to ATP Synthase and Regulates Permeability Transition 402.8.5 PT Activity Regulates Cardiac Development 412.8.6 Regulatory Molecules Do Not Form the Pore of mPTP 422.9 The mPTP: A Molecular Definition 432.9.1 The c]Subunit of F1FO ATP Synthase Comprises the PT Pore 432.9.2 The c]Subunit of ATP Synthase Creates the High Conductance mPTP Pore 452.9.3 F1 Regulates Biophysical Characteristics of the Purified c]Subunit 452.9.4 Structural Location of the Pore within the c]Subunit Ring 482.10 Closing of the mPTP May Enhance Mitochondrial Metabolic Plasticity and Regulate Synaptic Properties inHippocampal Neurons 492.11 mPTP Opening Correlates with Cell Death in Acute Ischemia, ROS Damage, or Glutamate Excitotoxicity 492.12 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? 512.13 S ynaptic Responses Decline during Long]Term Depression in Association with Bcl]2 Family]Regulated Mitochondrial Channel Activity 522.14 S ynapse Loss During Neurodegenerative Disease May Require Mitochondrial Channel Activity 532.15 Conclusions 54Acknowledgments 55References 553 Mitochondrial Channels in Neurodegeneration 65Pablo M. Peixoto, Kathleen W. Kinnally and Evgeny Pavlov3.1 Introduction 653.2 Mitochondrial Channels in the Healthy Neuron 663.2.1 Voltage Dependent Anion]Selective Channel is the Food Channel 663.2.2 Protein Import Channels 673.2.3 Mitochondrial Ca2+ Channels 743.2.4 Mrs2 – Mg2+ Channel 753.2.5 Mitochondrial K+ Channels 763.2.6 Mitochondrial Centum Pico]Siemens 763.2.7 Alkaline]Induced Anion]Selective Activity and Alkaline]Induced Anion]Selective Activity 773.2.8 Chloride Intracellular Channels 783.2.9 Alternative Ion Transport Pathways 783.3 Mitochondrial Channels in the Dying Cell 793.3.1 Apoptosis 793.3.2 Necrosis 803.4 Mitochondrial Channels in Neurodegenerative Diseases 833.5 Conclusions 87References 87Section II Control of Mitochondrial Signaling Networks 1014 Mitochondrial Ca2+ Transport in the Control of Neuronal Functions: Molecular and Cellular Mechanisms 103Yuriy M. Usachev4.1 Introduction 1034.2 Physiological and Pharmacological Characteristics of Mitochondrial Ca2+ Transport in Neurons 1064.3 Molecular Components of Mitochondrial Ca2+ Transport in Neurons 1104.4 Mitochondrial Ca2+ Signaling and Neuronal Excitability 1144.5 Mitochondrial Ca2+ Cycling in the Regulation of Synaptic Transmission 1154.6 Mitochondrial Ca2+ Transport and the Regulation of Gene Expression in Neurons 1184.7 Future Directions 119Acknowledgments 120References 1205 A MP]Activated Protein Kinase (AMPK) as a Cellular Energy Sensor and Therapeutic Target for Neuroprotection 130Petronela Weisová, Shona Pfeiffer and Jochen H. M. Prehn5.1 Introduction 1305.1.1 AMPK Expression, Structure, and Activity Regulation in Brain 1315.1.2 Other Roles for AMPK 1355.1.3 AMPK in Neurological Diseases and Neurodegeneration 1375.2 Conclusion and Future Perspectives 139References 1396 HDA C6: A Molecule with Multiple Functions in Neurodegenerative Diseases 146Yan Yan and Renjie Jiao6.1 Introduction 1466.2 Molecular Properties of HDAC6 1476.2.1 Classes of the HDAC Family 1476.2.2 HDAC6 1496.3 HDAC6 and Neurodegenerative Diseases 1516.3.1 HDAC6 and Elimination of Proteotoxicity in Neurodegenerative Diseases 1526.3.2 HDAC6 and Autophagic Clearance of Dysfunctional Mitochondria 1566.4 Perspectives 158References 1597 Neuronal Mitochondrial Transport 166Adam L. Knight, Yanmin Chen, Tao Sun and Zu]Hang Sheng7.1 Introduction 1667.2 Complex Motility Patterns of Axonal Mitochondria 1687.3 Mechanisms of Mitochondrial Transport 1697.3.1 Kinesin Motors and Anterograde Transport 1697.3.2 Dynein Motors and Retrograde Transport 1717.3.3 Interplay of Opposing Motor Proteins 1727.4 Mechanisms of Axonal Mitochondrial Anchoring 1727.5 Regulation of Mitochondrial Transport by Synaptic Activity 1737.6 Mitochondrial Transport and Synaptic Transmission 1747.7 Mitochondrial Transport and Presynaptic Variability 1757.8 Mitochondrial Transport and Axonal Branching 1767.9 Mitochondrial Transport and Mitophagy 1787.10 Conclusions and New Challenges 180Acknowledgments 180References 1818 Mitochondria in Control of Hypothalamic Metabolic Circuits 186Carole M. Nasrallah and Tamas L. Horvath8.1 Introduction 1868.2 Yin]Yang Relationship between Components of Hypothalamic Feeding and Satiety Circuits 1878.3 Mitochondria and Their Dynamics 1898.4 Metabolic Principles of Hunger and Satiety Promotion: Mitochondria in Support of Fat Versus Glucose Utilization 1918.5 Mitochondria Dynamics and Cellular Energetics 1938.5.1 Fission and Fusion of Mitochondria in Hypothalamic Feeding Circuits 1948.6 Mitochondrial Dysfunction and Metabolic Disorders 1968.7 Conclusions 197References 1979 Mitochondria Anchored at the Synapse 203George A. Spirou, Dakota Jackson and Guy A. Perkins9.1 Introduction 2039.2 Calibrated Positioning of Mitochondria 2049.3 Mitochondria and Crista Structure 2069.4 Adhering Junctions and Linkages to the Cytoskeleton 2089.5 Linkages of the OMM to the Mitochondrial Plaque and Reticulated Membrane 2109.6 Functions of the Organelle Complex 2119.7 MACs and Filamentous Contacts: A Continuum of Structure? 213Acknowledgments 214References 214Section III Defective Mitochondrial Dynamics and Mitophagy 21910 Neuronal Mitochondria are Different: Relevance to Neurodegenerative Disease 221Sarah B. Berman and J. Marie Hardwick10.1 Introduction 22110.2 Mitochondrial Dynamics in Neurons and Neurodegenerative Disease 22210.2.1 Quantifying Mitochondrial Dynamics 22210.2.2 Mutations and Toxins Alter Mitochondrial Dynamics in Neurological Disease 22310.3 Triggering Mitophagy in Neurons versus Other Cell Types 22610.3.1 Parkin Mitophagy Pathway Disease Genes 22610.3.2 Metabolic States of Neurons Modulate Mitophagy Induction 22710.3.3 Neurons Distinguish between Different Types of Mitochondrial Damage 22810.4 BCL]xL: The Guardian of Mitochondria 23110.4.1 BCL]xL Regulates Mitochondrial Dynamics and Neuronal Activity 23110.4.2 BCL]xL Regulates Mitochondrial Energetics 232Acknowledgments 233References 23311 PINK1 as a Sensor for Mitochondrial Function: Dual Roles 240Erin Steer, Michelle Dail and Charleen T. Chu11.1 Introduction 24011.2 PINK1 Promotes Mitochondrial Function 24111.3 Healthy Mitochondria Import and Process PINK1 24411.3.1 Localization and Processing of PINK1 Depends on an Intact ΔΨm 24411.4 Accumulation of Full Length]PINK1 as a Sensor of Mitochondrial Dysfunction 24511.5 Cytosolic PINK1 as a Sensor for Mitochondrial Function 24711.5.1 Cytosolic PINK1 Suppresses Cell Death and Autophagy/Mitophagy 24711.5.2 Cytosolic PINK1 Promotes Neurite Extension and Cell Survival 24811.6 PINK1 and Mitochondrial Dynamics 24811.7 Dual Roles for PINK1 as a Sensor of Mitochondrial Function and Dysfunction 249References 24912 A Get]Together to Tear It Apart: The Mitochondrion Meets the Cellular Turnover Machinery 254Gian]Luca McLelland and Edward A. Fon12.1 Mitochondrial Quality Control in Neurodegeneration 25412.2 An Overview of the Ubiquitin]Proteasome System 25512.3 Activities of the Cytosolic Proteasome at the Outer Mitochondrial Membrane 25612.4 The Turnover of Whole Mitochondria by Mitophagy 26012.5 Proteasomes and Phagophores Converge in the PINK1/parkin Pathway 26112.6 Implications of PINK1]/Parkin]Dependent Mitophagy in the Brain and in PD 26512.7 Emerging Mitochondrial Quality Control Mechanisms 267References 26813 Mitochondrial Involvement in Neurodegenerative Dementia 280Laura Bonanni, Valerio Frazzini, Astrid Thomas and Marco Onofrj13.1 Introduction 28013.2 Mitochondrial Dysfunction in Alzheimer Disease 28113.3 Mitochondrial Dysfunction, Bioenergetic Deficits, and Oxidative Stress in AD 28213.4 Mitochondrial Fragmentation in AD 28313.5 S ynaptic Mitochondria in AD 28313.6 Mitochondrial Dysfunction and Cationic Dyshomeostasis in AD 28413.7 Mitochondrial Dysfunction in DLB 28613.8 LRRK2 Mutations, Mitochondria and DLB 28713.9 Akinetic Crisis in Synucleinopathies is Linked to Genetic Mutations Involving Mitochondrial Proteins 28713.10 Conclusions 289References 289Section IV Mitochondria-Targeted Therapeutics and Model Systems 29514 Neuronal Mitochondria as a Target for the Discovery and Development of New Therapeutics 297Valentin K. Gribkoff14.1 Neurodegenerative Disorders and the Status of Drug Discovery 29714.2 Mitochondria as Targets for the Development of New NDD Therapies 30014.3 The Effects of Dexpramipexole on Mitochondrial Conductances: An Example of an Approach for ALS and Other NDDs 30114.3.1 ALS as a Therapeutic Target 30114.3.2 Mitochondrial Dysfunction in ALS 30314.3.3 Dexpramipexole and Bioenergetic Efficiency: Preclinical Studies 30314.3.4 Dexpramipexole in the Clinic 30914.4 What is the Future of a Mitochondrial Approach for NDD Therapy? 313Acknowledgments 314References 31515 Mitochondria as a Therapeutic Target for Alzheimer’s Disease 322Clara Hiu]Ling Hung, Sally Shuk]Yee Cheng, Simon Ming]Yuen Lee and Raymond Chuen]Chung Chang15.1 Introduction 32215.2 Mitochondrial Abnormalities and Dysfunction in Alzheimer’s Disease 32315.2.1 Mitochondrial Morphology and Ultrastructure 32315.2.2 Beta Amyloid, Tau, and Mitochondria 32315.2.3 Defective Mitochondria at Synapses 32515.2.4 Impaired Mitochondrial Dynamics 32515.2.5 Oxidative Stress 32615.2.6 Ca2+ Dysregulation in Mitochondria 32615.2.7 Mitochondrial Permeability Transition Pore 32715.3 Mitochondria as a Drug Target 32715.3.1 Targeting Drugs to Mitochondria 32715.3.2 Mitochondria]Targeted Antioxidants 32915.3.3 Mitochondrial Ca2+ Pathways 33015.3.4 Mitochondrial Permeability Transition Pore 33115.3.5 Mitochondrial Dynamics 33115.3.6 Mitochondrial Metabolism 33215.3.7 Mitochondrial Biogenesis 33215.3.8 Limitations of Mitochondrial]Targeted Drugs 33315.4 Conclusions 333Acknowledgments 333References 33416 Mitochondria in Parkinson’s Disease 339Giuseppe Arena and Enza Maria Valente16.1 Introduction 33916.2 Role of Mitochondria in Sporadic PD 34016.2.1 Complex I Deficiency and mtDNA Defects 34016.2.2 Oxidative Stress and ROS Production 34116.3 Mitochondrial Dysfunction in Monogenic PD 34216.3.1 Autosomal Dominant PD 34316.3.2 Autosomal Recessive PD 34616.4 Conclusions 350References 35117 Therapeutic Targeting of Neuronal Mitochondria in Brain Injury 359Heather M. Yonutas, Edward D. Hall and Patrick G. Sullivan17.1 Introduction 35917.2 Mitochondria Bioenergetics 36017.3 Traumatic Brain Injury 36317.3.1 Models of TBI 36417.3.2 Secondary Injury Cascade of TBI 36617.4 Pharmaceutical Interventions 37017.4.1 Targeting Mitochondrial Dysfunction 37017.4.2 Targeting Oxidative Stress 37117.4.3 Interventions with Multiple Targets 37217.5 Conclusion 372References 37318 The Use of Fibroblasts from Patients with Inherited Mitochondrial Disorders for Pathomechanistic Studies and Evaluation of Therapies 378Devorah Soiferman and Ann Saada18.1 Introduction 37818.1.1 Identification of Mitochondrial Disorders 38018.1.2 Pathomechanism of Mitochondrial Disorders 38118.1.3 Treatment of Mitochondrial Disorders 38218.1.4 Models of Mitochondrial Disorders 38318.2 Pathomechanistic Studies of Mitochondrial Disorders in Patients’ Fibroblasts 38518.2.1 Reduced Cellular ATP 38518.2.2 Increased Oxidative Stress 38618.2.3 Reduction of Mitochondrial Membrane Potential 38618.2.4 Disruption of Calcium Homeostasis 38618.2.5 Coenzyme Q10 Deficiency 38718.2.6 Mitochondrial Dynamics and Mitophagy 38718.3 Evaluation of Therapeutic Options Using Patient Derived Fibroblasts 38818.3.1 Pharmacological Approaches 38818.3.2 Genetic Manipulation 39118.4 Conclusion 392Acknowledgments 393References 393Index 399

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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• Contributors xivPreface xviiiSection I Mitochondrial Structure and Ion Channels 11 Mitochondrial Permeability Transition: A Look From a Different Angle 3Nickolay Brustovetsky1.1 Regulation of Intracellular Calcium in Neurons 31.2 Calcium Overload and Mitochondrial Permeability Transition 41.3 The Mitochondrial Transition Pore 81.3.1 Evidence for ANT and VDAC as Components of the PTP 81.3.2 Alternative Hypotheses of mPTP Composition 17Acknowledgments 22References 222 The Mitochondrial Permeability Transition Pore, the c]Subunit of the F1FO AT P Synthase, Cellular Development, and Synaptic Efficiency 31Elizabeth A. Jonas, George A. Porter, Jr., Gisela Beutner, Nelli Mnatsakanyan and Kambiz N. Alavian2.1 Introduction 322.2 Mitochondria at the Center of Cell Metabolism and Cell Death 322.3 Mitochondrial Inner Membrane Leak: Regulator of Metabolic Rate and Uncoupling 322.4 Mitochondrial Inner Membrane Channels and Exchangers are Necessary for Ca2+ Cycling and Cellular Ca2+ Dynamics 332.5 Mitochondrial Inner and Outer Membrane Channel Activity Regulates Ca2+ Re]Release from Mitochondria after Buffering 342.6 Bcl]2 Family Proteins Regulate Pathological Outer Mitochondrial Membrane Permeabilization (MOMP) 352.7 Pathological Inner Membrane Depolarization: Mitochondrial Permeability Transition 362.8 The Quest for an Inner Membrane Ca2+]Sensitive Uncoupling Channel: The PT Pore 372.8.1 Electrophysiologic Properties of the mPTP 372.8.2 Characterization of a Molecular Complex Regulating the Pore 392.8.3 Bcl]xL Regulates Metabolic Efficiency by Binding to the β]Subunit of the ATP Synthase 392.8.4 CypD Binds to ATP Synthase and Regulates Permeability Transition 402.8.5 PT Activity Regulates Cardiac Development 412.8.6 Regulatory Molecules Do Not Form the Pore of mPTP 422.9 The mPTP: A Molecular Definition 432.9.1 The c]Subunit of F1FO ATP Synthase Comprises the PT Pore 432.9.2 The c]Subunit of ATP Synthase Creates the High Conductance mPTP Pore 452.9.3 F1 Regulates Biophysical Characteristics of the Purified c]Subunit 452.9.4 Structural Location of the Pore within the c]Subunit Ring 482.10 Closing of the mPTP May Enhance Mitochondrial Metabolic Plasticity and Regulate Synaptic Properties inHippocampal Neurons 492.11 mPTP Opening Correlates with Cell Death in Acute Ischemia, ROS Damage, or Glutamate Excitotoxicity 492.12 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? 512.13 S ynaptic Responses Decline during Long]Term Depression in Association with Bcl]2 Family]Regulated Mitochondrial Channel Activity 522.14 S ynapse Loss During Neurodegenerative Disease May Require Mitochondrial Channel Activity 532.15 Conclusions 54Acknowledgments 55References 553 Mitochondrial Channels in Neurodegeneration 65Pablo M. Peixoto, Kathleen W. Kinnally and Evgeny Pavlov3.1 Introduction 653.2 Mitochondrial Channels in the Healthy Neuron 663.2.1 Voltage Dependent Anion]Selective Channel is the Food Channel 663.2.2 Protein Import Channels 673.2.3 Mitochondrial Ca2+ Channels 743.2.4 Mrs2 – Mg2+ Channel 753.2.5 Mitochondrial K+ Channels 763.2.6 Mitochondrial Centum Pico]Siemens 763.2.7 Alkaline]Induced Anion]Selective Activity and Alkaline]Induced Anion]Selective Activity 773.2.8 Chloride Intracellular Channels 783.2.9 Alternative Ion Transport Pathways 783.3 Mitochondrial Channels in the Dying Cell 793.3.1 Apoptosis 793.3.2 Necrosis 803.4 Mitochondrial Channels in Neurodegenerative Diseases 833.5 Conclusions 87References 87Section II Control of Mitochondrial Signaling Networks 1014 Mitochondrial Ca2+ Transport in the Control of Neuronal Functions: Molecular and Cellular Mechanisms 103Yuriy M. Usachev4.1 Introduction 1034.2 Physiological and Pharmacological Characteristics of Mitochondrial Ca2+ Transport in Neurons 1064.3 Molecular Components of Mitochondrial Ca2+ Transport in Neurons 1104.4 Mitochondrial Ca2+ Signaling and Neuronal Excitability 1144.5 Mitochondrial Ca2+ Cycling in the Regulation of Synaptic Transmission 1154.6 Mitochondrial Ca2+ Transport and the Regulation of Gene Expression in Neurons 1184.7 Future Directions 119Acknowledgments 120References 1205 A MP]Activated Protein Kinase (AMPK) as a Cellular Energy Sensor and Therapeutic Target for Neuroprotection 130Petronela Weisová, Shona Pfeiffer and Jochen H. M. Prehn5.1 Introduction 1305.1.1 AMPK Expression, Structure, and Activity Regulation in Brain 1315.1.2 Other Roles for AMPK 1355.1.3 AMPK in Neurological Diseases and Neurodegeneration 1375.2 Conclusion and Future Perspectives 139References 1396 HDA C6: A Molecule with Multiple Functions in Neurodegenerative Diseases 146Yan Yan and Renjie Jiao6.1 Introduction 1466.2 Molecular Properties of HDAC6 1476.2.1 Classes of the HDAC Family 1476.2.2 HDAC6 1496.3 HDAC6 and Neurodegenerative Diseases 1516.3.1 HDAC6 and Elimination of Proteotoxicity in Neurodegenerative Diseases 1526.3.2 HDAC6 and Autophagic Clearance of Dysfunctional Mitochondria 1566.4 Perspectives 158References 1597 Neuronal Mitochondrial Transport 166Adam L. Knight, Yanmin Chen, Tao Sun and Zu]Hang Sheng7.1 Introduction 1667.2 Complex Motility Patterns of Axonal Mitochondria 1687.3 Mechanisms of Mitochondrial Transport 1697.3.1 Kinesin Motors and Anterograde Transport 1697.3.2 Dynein Motors and Retrograde Transport 1717.3.3 Interplay of Opposing Motor Proteins 1727.4 Mechanisms of Axonal Mitochondrial Anchoring 1727.5 Regulation of Mitochondrial Transport by Synaptic Activity 1737.6 Mitochondrial Transport and Synaptic Transmission 1747.7 Mitochondrial Transport and Presynaptic Variability 1757.8 Mitochondrial Transport and Axonal Branching 1767.9 Mitochondrial Transport and Mitophagy 1787.10 Conclusions and New Challenges 180Acknowledgments 180References 1818 Mitochondria in Control of Hypothalamic Metabolic Circuits 186Carole M. Nasrallah and Tamas L. Horvath8.1 Introduction 1868.2 Yin]Yang Relationship between Components of Hypothalamic Feeding and Satiety Circuits 1878.3 Mitochondria and Their Dynamics 1898.4 Metabolic Principles of Hunger and Satiety Promotion: Mitochondria in Support of Fat Versus Glucose Utilization 1918.5 Mitochondria Dynamics and Cellular Energetics 1938.5.1 Fission and Fusion of Mitochondria in Hypothalamic Feeding Circuits 1948.6 Mitochondrial Dysfunction and Metabolic Disorders 1968.7 Conclusions 197References 1979 Mitochondria Anchored at the Synapse 203George A. Spirou, Dakota Jackson and Guy A. Perkins9.1 Introduction 2039.2 Calibrated Positioning of Mitochondria 2049.3 Mitochondria and Crista Structure 2069.4 Adhering Junctions and Linkages to the Cytoskeleton 2089.5 Linkages of the OMM to the Mitochondrial Plaque and Reticulated Membrane 2109.6 Functions of the Organelle Complex 2119.7 MACs and Filamentous Contacts: A Continuum of Structure? 213Acknowledgments 214References 214Section III Defective Mitochondrial Dynamics and Mitophagy 21910 Neuronal Mitochondria are Different: Relevance to Neurodegenerative Disease 221Sarah B. Berman and J. Marie Hardwick10.1 Introduction 22110.2 Mitochondrial Dynamics in Neurons and Neurodegenerative Disease 22210.2.1 Quantifying Mitochondrial Dynamics 22210.2.2 Mutations and Toxins Alter Mitochondrial Dynamics in Neurological Disease 22310.3 Triggering Mitophagy in Neurons versus Other Cell Types 22610.3.1 Parkin Mitophagy Pathway Disease Genes 22610.3.2 Metabolic States of Neurons Modulate Mitophagy Induction 22710.3.3 Neurons Distinguish between Different Types of Mitochondrial Damage 22810.4 BCL]xL: The Guardian of Mitochondria 23110.4.1 BCL]xL Regulates Mitochondrial Dynamics and Neuronal Activity 23110.4.2 BCL]xL Regulates Mitochondrial Energetics 232Acknowledgments 233References 23311 PINK1 as a Sensor for Mitochondrial Function: Dual Roles 240Erin Steer, Michelle Dail and Charleen T. Chu11.1 Introduction 24011.2 PINK1 Promotes Mitochondrial Function 24111.3 Healthy Mitochondria Import and Process PINK1 24411.3.1 Localization and Processing of PINK1 Depends on an Intact ΔΨm 24411.4 Accumulation of Full Length]PINK1 as a Sensor of Mitochondrial Dysfunction 24511.5 Cytosolic PINK1 as a Sensor for Mitochondrial Function 24711.5.1 Cytosolic PINK1 Suppresses Cell Death and Autophagy/Mitophagy 24711.5.2 Cytosolic PINK1 Promotes Neurite Extension and Cell Survival 24811.6 PINK1 and Mitochondrial Dynamics 24811.7 Dual Roles for PINK1 as a Sensor of Mitochondrial Function and Dysfunction 249References 24912 A Get]Together to Tear It Apart: The Mitochondrion Meets the Cellular Turnover Machinery 254Gian]Luca McLelland and Edward A. Fon12.1 Mitochondrial Quality Control in Neurodegeneration 25412.2 An Overview of the Ubiquitin]Proteasome System 25512.3 Activities of the Cytosolic Proteasome at the Outer Mitochondrial Membrane 25612.4 The Turnover of Whole Mitochondria by Mitophagy 26012.5 Proteasomes and Phagophores Converge in the PINK1/parkin Pathway 26112.6 Implications of PINK1]/Parkin]Dependent Mitophagy in the Brain and in PD 26512.7 Emerging Mitochondrial Quality Control Mechanisms 267References 26813 Mitochondrial Involvement in Neurodegenerative Dementia 280Laura Bonanni, Valerio Frazzini, Astrid Thomas and Marco Onofrj13.1 Introduction 28013.2 Mitochondrial Dysfunction in Alzheimer Disease 28113.3 Mitochondrial Dysfunction, Bioenergetic Deficits, and Oxidative Stress in AD 28213.4 Mitochondrial Fragmentation in AD 28313.5 S ynaptic Mitochondria in AD 28313.6 Mitochondrial Dysfunction and Cationic Dyshomeostasis in AD 28413.7 Mitochondrial Dysfunction in DLB 28613.8 LRRK2 Mutations, Mitochondria and DLB 28713.9 Akinetic Crisis in Synucleinopathies is Linked to Genetic Mutations Involving Mitochondrial Proteins 28713.10 Conclusions 289References 289Section IV Mitochondria-Targeted Therapeutics and Model Systems 29514 Neuronal Mitochondria as a Target for the Discovery and Development of New Therapeutics 297Valentin K. Gribkoff14.1 Neurodegenerative Disorders and the Status of Drug Discovery 29714.2 Mitochondria as Targets for the Development of New NDD Therapies 30014.3 The Effects of Dexpramipexole on Mitochondrial Conductances: An Example of an Approach for ALS and Other NDDs 30114.3.1 ALS as a Therapeutic Target 30114.3.2 Mitochondrial Dysfunction in ALS 30314.3.3 Dexpramipexole and Bioenergetic Efficiency: Preclinical Studies 30314.3.4 Dexpramipexole in the Clinic 30914.4 What is the Future of a Mitochondrial Approach for NDD Therapy? 313Acknowledgments 314References 31515 Mitochondria as a Therapeutic Target for Alzheimer’s Disease 322Clara Hiu]Ling Hung, Sally Shuk]Yee Cheng, Simon Ming]Yuen Lee and Raymond Chuen]Chung Chang15.1 Introduction 32215.2 Mitochondrial Abnormalities and Dysfunction in Alzheimer’s Disease 32315.2.1 Mitochondrial Morphology and Ultrastructure 32315.2.2 Beta Amyloid, Tau, and Mitochondria 32315.2.3 Defective Mitochondria at Synapses 32515.2.4 Impaired Mitochondrial Dynamics 32515.2.5 Oxidative Stress 32615.2.6 Ca2+ Dysregulation in Mitochondria 32615.2.7 Mitochondrial Permeability Transition Pore 32715.3 Mitochondria as a Drug Target 32715.3.1 Targeting Drugs to Mitochondria 32715.3.2 Mitochondria]Targeted Antioxidants 32915.3.3 Mitochondrial Ca2+ Pathways 33015.3.4 Mitochondrial Permeability Transition Pore 33115.3.5 Mitochondrial Dynamics 33115.3.6 Mitochondrial Metabolism 33215.3.7 Mitochondrial Biogenesis 33215.3.8 Limitations of Mitochondrial]Targeted Drugs 33315.4 Conclusions 333Acknowledgments 333References 33416 Mitochondria in Parkinson’s Disease 339Giuseppe Arena and Enza Maria Valente16.1 Introduction 33916.2 Role of Mitochondria in Sporadic PD 34016.2.1 Complex I Deficiency and mtDNA Defects 34016.2.2 Oxidative Stress and ROS Production 34116.3 Mitochondrial Dysfunction in Monogenic PD 34216.3.1 Autosomal Dominant PD 34316.3.2 Autosomal Recessive PD 34616.4 Conclusions 350References 35117 Therapeutic Targeting of Neuronal Mitochondria in Brain Injury 359Heather M. Yonutas, Edward D. Hall and Patrick G. Sullivan17.1 Introduction 35917.2 Mitochondria Bioenergetics 36017.3 Traumatic Brain Injury 36317.3.1 Models of TBI 36417.3.2 Secondary Injury Cascade of TBI 36617.4 Pharmaceutical Interventions 37017.4.1 Targeting Mitochondrial Dysfunction 37017.4.2 Targeting Oxidative Stress 37117.4.3 Interventions with Multiple Targets 37217.5 Conclusion 372References 37318 The Use of Fibroblasts from Patients with Inherited Mitochondrial Disorders for Pathomechanistic Studies and Evaluation of Therapies 378Devorah Soiferman and Ann Saada18.1 Introduction 37818.1.1 Identification of Mitochondrial Disorders 38018.1.2 Pathomechanism of Mitochondrial Disorders 38118.1.3 Treatment of Mitochondrial Disorders 38218.1.4 Models of Mitochondrial Disorders 38318.2 Pathomechanistic Studies of Mitochondrial Disorders in Patients’ Fibroblasts 38518.2.1 Reduced Cellular ATP 38518.2.2 Increased Oxidative Stress 38618.2.3 Reduction of Mitochondrial Membrane Potential 38618.2.4 Disruption of Calcium Homeostasis 38618.2.5 Coenzyme Q10 Deficiency 38718.2.6 Mitochondrial Dynamics and Mitophagy 38718.3 Evaluation of Therapeutic Options Using Patient Derived Fibroblasts 38818.3.1 Pharmacological Approaches 38818.3.2 Genetic Manipulation 39118.4 Conclusion 392Acknowledgments 393References 393Index 399

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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• Contributors xivPreface xviiiSection I Mitochondrial Structure and Ion Channels 11 Mitochondrial Permeability Transition: A Look From a Different Angle 3Nickolay Brustovetsky1.1 Regulation of Intracellular Calcium in Neurons 31.2 Calcium Overload and Mitochondrial Permeability Transition 41.3 The Mitochondrial Transition Pore 81.3.1 Evidence for ANT and VDAC as Components of the PTP 81.3.2 Alternative Hypotheses of mPTP Composition 17Acknowledgments 22References 222 The Mitochondrial Permeability Transition Pore, the c]Subunit of the F1FO AT P Synthase, Cellular Development, and Synaptic Efficiency 31Elizabeth A. Jonas, George A. Porter, Jr., Gisela Beutner, Nelli Mnatsakanyan and Kambiz N. Alavian2.1 Introduction 322.2 Mitochondria at the Center of Cell Metabolism and Cell Death 322.3 Mitochondrial Inner Membrane Leak: Regulator of Metabolic Rate and Uncoupling 322.4 Mitochondrial Inner Membrane Channels and Exchangers are Necessary for Ca2+ Cycling and Cellular Ca2+ Dynamics 332.5 Mitochondrial Inner and Outer Membrane Channel Activity Regulates Ca2+ Re]Release from Mitochondria after Buffering 342.6 Bcl]2 Family Proteins Regulate Pathological Outer Mitochondrial Membrane Permeabilization (MOMP) 352.7 Pathological Inner Membrane Depolarization: Mitochondrial Permeability Transition 362.8 The Quest for an Inner Membrane Ca2+]Sensitive Uncoupling Channel: The PT Pore 372.8.1 Electrophysiologic Properties of the mPTP 372.8.2 Characterization of a Molecular Complex Regulating the Pore 392.8.3 Bcl]xL Regulates Metabolic Efficiency by Binding to the β]Subunit of the ATP Synthase 392.8.4 CypD Binds to ATP Synthase and Regulates Permeability Transition 402.8.5 PT Activity Regulates Cardiac Development 412.8.6 Regulatory Molecules Do Not Form the Pore of mPTP 422.9 The mPTP: A Molecular Definition 432.9.1 The c]Subunit of F1FO ATP Synthase Comprises the PT Pore 432.9.2 The c]Subunit of ATP Synthase Creates the High Conductance mPTP Pore 452.9.3 F1 Regulates Biophysical Characteristics of the Purified c]Subunit 452.9.4 Structural Location of the Pore within the c]Subunit Ring 482.10 Closing of the mPTP May Enhance Mitochondrial Metabolic Plasticity and Regulate Synaptic Properties inHippocampal Neurons 492.11 mPTP Opening Correlates with Cell Death in Acute Ischemia, ROS Damage, or Glutamate Excitotoxicity 492.12 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? 512.13 S ynaptic Responses Decline during Long]Term Depression in Association with Bcl]2 Family]Regulated Mitochondrial Channel Activity 522.14 S ynapse Loss During Neurodegenerative Disease May Require Mitochondrial Channel Activity 532.15 Conclusions 54Acknowledgments 55References 553 Mitochondrial Channels in Neurodegeneration 65Pablo M. Peixoto, Kathleen W. Kinnally and Evgeny Pavlov3.1 Introduction 653.2 Mitochondrial Channels in the Healthy Neuron 663.2.1 Voltage Dependent Anion]Selective Channel is the Food Channel 663.2.2 Protein Import Channels 673.2.3 Mitochondrial Ca2+ Channels 743.2.4 Mrs2 – Mg2+ Channel 753.2.5 Mitochondrial K+ Channels 763.2.6 Mitochondrial Centum Pico]Siemens 763.2.7 Alkaline]Induced Anion]Selective Activity and Alkaline]Induced Anion]Selective Activity 773.2.8 Chloride Intracellular Channels 783.2.9 Alternative Ion Transport Pathways 783.3 Mitochondrial Channels in the Dying Cell 793.3.1 Apoptosis 793.3.2 Necrosis 803.4 Mitochondrial Channels in Neurodegenerative Diseases 833.5 Conclusions 87References 87Section II Control of Mitochondrial Signaling Networks 1014 Mitochondrial Ca2+ Transport in the Control of Neuronal Functions: Molecular and Cellular Mechanisms 103Yuriy M. Usachev4.1 Introduction 1034.2 Physiological and Pharmacological Characteristics of Mitochondrial Ca2+ Transport in Neurons 1064.3 Molecular Components of Mitochondrial Ca2+ Transport in Neurons 1104.4 Mitochondrial Ca2+ Signaling and Neuronal Excitability 1144.5 Mitochondrial Ca2+ Cycling in the Regulation of Synaptic Transmission 1154.6 Mitochondrial Ca2+ Transport and the Regulation of Gene Expression in Neurons 1184.7 Future Directions 119Acknowledgments 120References 1205 A MP]Activated Protein Kinase (AMPK) as a Cellular Energy Sensor and Therapeutic Target for Neuroprotection 130Petronela Weisová, Shona Pfeiffer and Jochen H. M. Prehn5.1 Introduction 1305.1.1 AMPK Expression, Structure, and Activity Regulation in Brain 1315.1.2 Other Roles for AMPK 1355.1.3 AMPK in Neurological Diseases and Neurodegeneration 1375.2 Conclusion and Future Perspectives 139References 1396 HDA C6: A Molecule with Multiple Functions in Neurodegenerative Diseases 146Yan Yan and Renjie Jiao6.1 Introduction 1466.2 Molecular Properties of HDAC6 1476.2.1 Classes of the HDAC Family 1476.2.2 HDAC6 1496.3 HDAC6 and Neurodegenerative Diseases 1516.3.1 HDAC6 and Elimination of Proteotoxicity in Neurodegenerative Diseases 1526.3.2 HDAC6 and Autophagic Clearance of Dysfunctional Mitochondria 1566.4 Perspectives 158References 1597 Neuronal Mitochondrial Transport 166Adam L. Knight, Yanmin Chen, Tao Sun and Zu]Hang Sheng7.1 Introduction 1667.2 Complex Motility Patterns of Axonal Mitochondria 1687.3 Mechanisms of Mitochondrial Transport 1697.3.1 Kinesin Motors and Anterograde Transport 1697.3.2 Dynein Motors and Retrograde Transport 1717.3.3 Interplay of Opposing Motor Proteins 1727.4 Mechanisms of Axonal Mitochondrial Anchoring 1727.5 Regulation of Mitochondrial Transport by Synaptic Activity 1737.6 Mitochondrial Transport and Synaptic Transmission 1747.7 Mitochondrial Transport and Presynaptic Variability 1757.8 Mitochondrial Transport and Axonal Branching 1767.9 Mitochondrial Transport and Mitophagy 1787.10 Conclusions and New Challenges 180Acknowledgments 180References 1818 Mitochondria in Control of Hypothalamic Metabolic Circuits 186Carole M. Nasrallah and Tamas L. Horvath8.1 Introduction 1868.2 Yin]Yang Relationship between Components of Hypothalamic Feeding and Satiety Circuits 1878.3 Mitochondria and Their Dynamics 1898.4 Metabolic Principles of Hunger and Satiety Promotion: Mitochondria in Support of Fat Versus Glucose Utilization 1918.5 Mitochondria Dynamics and Cellular Energetics 1938.5.1 Fission and Fusion of Mitochondria in Hypothalamic Feeding Circuits 1948.6 Mitochondrial Dysfunction and Metabolic Disorders 1968.7 Conclusions 197References 1979 Mitochondria Anchored at the Synapse 203George A. Spirou, Dakota Jackson and Guy A. Perkins9.1 Introduction 2039.2 Calibrated Positioning of Mitochondria 2049.3 Mitochondria and Crista Structure 2069.4 Adhering Junctions and Linkages to the Cytoskeleton 2089.5 Linkages of the OMM to the Mitochondrial Plaque and Reticulated Membrane 2109.6 Functions of the Organelle Complex 2119.7 MACs and Filamentous Contacts: A Continuum of Structure? 213Acknowledgments 214References 214Section III Defective Mitochondrial Dynamics and Mitophagy 21910 Neuronal Mitochondria are Different: Relevance to Neurodegenerative Disease 221Sarah B. Berman and J. Marie Hardwick10.1 Introduction 22110.2 Mitochondrial Dynamics in Neurons and Neurodegenerative Disease 22210.2.1 Quantifying Mitochondrial Dynamics 22210.2.2 Mutations and Toxins Alter Mitochondrial Dynamics in Neurological Disease 22310.3 Triggering Mitophagy in Neurons versus Other Cell Types 22610.3.1 Parkin Mitophagy Pathway Disease Genes 22610.3.2 Metabolic States of Neurons Modulate Mitophagy Induction 22710.3.3 Neurons Distinguish between Different Types of Mitochondrial Damage 22810.4 BCL]xL: The Guardian of Mitochondria 23110.4.1 BCL]xL Regulates Mitochondrial Dynamics and Neuronal Activity 23110.4.2 BCL]xL Regulates Mitochondrial Energetics 232Acknowledgments 233References 23311 PINK1 as a Sensor for Mitochondrial Function: Dual Roles 240Erin Steer, Michelle Dail and Charleen T. Chu11.1 Introduction 24011.2 PINK1 Promotes Mitochondrial Function 24111.3 Healthy Mitochondria Import and Process PINK1 24411.3.1 Localization and Processing of PINK1 Depends on an Intact ΔΨm 24411.4 Accumulation of Full Length]PINK1 as a Sensor of Mitochondrial Dysfunction 24511.5 Cytosolic PINK1 as a Sensor for Mitochondrial Function 24711.5.1 Cytosolic PINK1 Suppresses Cell Death and Autophagy/Mitophagy 24711.5.2 Cytosolic PINK1 Promotes Neurite Extension and Cell Survival 24811.6 PINK1 and Mitochondrial Dynamics 24811.7 Dual Roles for PINK1 as a Sensor of Mitochondrial Function and Dysfunction 249References 24912 A Get]Together to Tear It Apart: The Mitochondrion Meets the Cellular Turnover Machinery 254Gian]Luca McLelland and Edward A. Fon12.1 Mitochondrial Quality Control in Neurodegeneration 25412.2 An Overview of the Ubiquitin]Proteasome System 25512.3 Activities of the Cytosolic Proteasome at the Outer Mitochondrial Membrane 25612.4 The Turnover of Whole Mitochondria by Mitophagy 26012.5 Proteasomes and Phagophores Converge in the PINK1/parkin Pathway 26112.6 Implications of PINK1]/Parkin]Dependent Mitophagy in the Brain and in PD 26512.7 Emerging Mitochondrial Quality Control Mechanisms 267References 26813 Mitochondrial Involvement in Neurodegenerative Dementia 280Laura Bonanni, Valerio Frazzini, Astrid Thomas and Marco Onofrj13.1 Introduction 28013.2 Mitochondrial Dysfunction in Alzheimer Disease 28113.3 Mitochondrial Dysfunction, Bioenergetic Deficits, and Oxidative Stress in AD 28213.4 Mitochondrial Fragmentation in AD 28313.5 S ynaptic Mitochondria in AD 28313.6 Mitochondrial Dysfunction and Cationic Dyshomeostasis in AD 28413.7 Mitochondrial Dysfunction in DLB 28613.8 LRRK2 Mutations, Mitochondria and DLB 28713.9 Akinetic Crisis in Synucleinopathies is Linked to Genetic Mutations Involving Mitochondrial Proteins 28713.10 Conclusions 289References 289Section IV Mitochondria-Targeted Therapeutics and Model Systems 29514 Neuronal Mitochondria as a Target for the Discovery and Development of New Therapeutics 297Valentin K. Gribkoff14.1 Neurodegenerative Disorders and the Status of Drug Discovery 29714.2 Mitochondria as Targets for the Development of New NDD Therapies 30014.3 The Effects of Dexpramipexole on Mitochondrial Conductances: An Example of an Approach for ALS and Other NDDs 30114.3.1 ALS as a Therapeutic Target 30114.3.2 Mitochondrial Dysfunction in ALS 30314.3.3 Dexpramipexole and Bioenergetic Efficiency: Preclinical Studies 30314.3.4 Dexpramipexole in the Clinic 30914.4 What is the Future of a Mitochondrial Approach for NDD Therapy? 313Acknowledgments 314References 31515 Mitochondria as a Therapeutic Target for Alzheimer’s Disease 322Clara Hiu]Ling Hung, Sally Shuk]Yee Cheng, Simon Ming]Yuen Lee and Raymond Chuen]Chung Chang15.1 Introduction 32215.2 Mitochondrial Abnormalities and Dysfunction in Alzheimer’s Disease 32315.2.1 Mitochondrial Morphology and Ultrastructure 32315.2.2 Beta Amyloid, Tau, and Mitochondria 32315.2.3 Defective Mitochondria at Synapses 32515.2.4 Impaired Mitochondrial Dynamics 32515.2.5 Oxidative Stress 32615.2.6 Ca2+ Dysregulation in Mitochondria 32615.2.7 Mitochondrial Permeability Transition Pore 32715.3 Mitochondria as a Drug Target 32715.3.1 Targeting Drugs to Mitochondria 32715.3.2 Mitochondria]Targeted Antioxidants 32915.3.3 Mitochondrial Ca2+ Pathways 33015.3.4 Mitochondrial Permeability Transition Pore 33115.3.5 Mitochondrial Dynamics 33115.3.6 Mitochondrial Metabolism 33215.3.7 Mitochondrial Biogenesis 33215.3.8 Limitations of Mitochondrial]Targeted Drugs 33315.4 Conclusions 333Acknowledgments 333References 33416 Mitochondria in Parkinson’s Disease 339Giuseppe Arena and Enza Maria Valente16.1 Introduction 33916.2 Role of Mitochondria in Sporadic PD 34016.2.1 Complex I Deficiency and mtDNA Defects 34016.2.2 Oxidative Stress and ROS Production 34116.3 Mitochondrial Dysfunction in Monogenic PD 34216.3.1 Autosomal Dominant PD 34316.3.2 Autosomal Recessive PD 34616.4 Conclusions 350References 35117 Therapeutic Targeting of Neuronal Mitochondria in Brain Injury 359Heather M. Yonutas, Edward D. Hall and Patrick G. Sullivan17.1 Introduction 35917.2 Mitochondria Bioenergetics 36017.3 Traumatic Brain Injury 36317.3.1 Models of TBI 36417.3.2 Secondary Injury Cascade of TBI 36617.4 Pharmaceutical Interventions 37017.4.1 Targeting Mitochondrial Dysfunction 37017.4.2 Targeting Oxidative Stress 37117.4.3 Interventions with Multiple Targets 37217.5 Conclusion 372References 37318 The Use of Fibroblasts from Patients with Inherited Mitochondrial Disorders for Pathomechanistic Studies and Evaluation of Therapies 378Devorah Soiferman and Ann Saada18.1 Introduction 37818.1.1 Identification of Mitochondrial Disorders 38018.1.2 Pathomechanism of Mitochondrial Disorders 38118.1.3 Treatment of Mitochondrial Disorders 38218.1.4 Models of Mitochondrial Disorders 38318.2 Pathomechanistic Studies of Mitochondrial Disorders in Patients’ Fibroblasts 38518.2.1 Reduced Cellular ATP 38518.2.2 Increased Oxidative Stress 38618.2.3 Reduction of Mitochondrial Membrane Potential 38618.2.4 Disruption of Calcium Homeostasis 38618.2.5 Coenzyme Q10 Deficiency 38718.2.6 Mitochondrial Dynamics and Mitophagy 38718.3 Evaluation of Therapeutic Options Using Patient Derived Fibroblasts 38818.3.1 Pharmacological Approaches 38818.3.2 Genetic Manipulation 39118.4 Conclusion 392Acknowledgments 393References 393Index 399