Springer-Verlag Berlin Heidelberg GmbH

Keshav K. Singh (Ed.)

Mitochondrial DNA Mutations in Aging, Disease and Cancer

, Springer

Keshav K. Singh, Ph.D. The Divisions of Experimental Therapeutics and Radiation Oncology Johns Hopkins Oncology Center and Department of Environmental Health Johns Hopkins School of Public Health 600 N. Wolfe Street, Room 2-121

Baltimore, Maryland, 21287 U.S.A.

Library of Congress Cataloging-in-Publication data

Mitochondrial DNA mutations in aging, disease, and cancer / Keshav K. Singh ... [et al.). p. cm.-(Medical intelligence unit)

Includes bibliographical references and index. ISBN 978-3-662-12511-3 ISBN 978-3-662-12509-0 (eBook) DOI 10.1007/978-3-662-12509-0

1. Mitochondrial DNA-Abnormalities. 2. Mitochondrial DNA. 3. Mitochondrial pathology. 4. Neoplasms-genetics. I. Singh, Keshav K. II. Series.

[DNLM: 1. DNA, Mitochondrial. 2. Mutation. 3. Mitochondria-genetics. 4. Mitochondria-pathology. 5. Aging-genetics. QU 58·5 M684 1998 RBI55.5·M584 1998 616'.042- 21 DNLM/DLC 97-50433 for Library of Congress CIP

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DEDICATION

To Babuji and Mai

ACKNOWLEDGMENTS

I am greatly indebted to the contributing authors for their enthusiasm, cooperation, and the responsibil­ity they took in writing the chapters in their area of ex­pertise. I thank my colleagues Orest Hurko, Al Lewin, Larry Grossman, Kylie Keshav, Moody Wharam, Jerry Williams, Steve Howard, Larry Dillehay, J ames Vager, James Vornov, Leona Samson, Bruce Dempie, Mamata Gokhale, and Sreekant Gokhale for many stimulating dis­cussions on mitochondrial biology and disease. I am also grateful to Cindy Morin for secretarial assistance and to the members of my laboratory, in particular Grace Kim, Hok Koe and Albert Jung for conducting literature searches. Finally, I thank my family for their patience and support while putting together this mono graph.

======PREFACE =====

The molecular basis for mitochondrial diseases remained unclear for years after Luft and colleagues described the first mitochondrial dis­

ease. Within the last 10 years, however, our understanding of mitochon­drial diseases has grown tremendously, beginning with reports in 1988 that mutations in mitochondrial DNA (mtDNA) are present in patients with Kearns-Sayre syndrome and Leber's hereditary optic neuropathy. Since then, mutations in mtDNA have been found in numerous dis­eases with a variety of clinical symptoms, such as ataxia, retinopathy, blindness, deafness, diabetes, cardiomyopathy, and skeletal and ocular myopathies. Mutations in mtDNA are also associated with aging and neuro degenerative diseases, and recently, altered mitochondrial func­tion was reported to play an important role in programmed cell death and cancer. Since the majority of the pro teins important for mitochon­drial function are encoded by nuclear genes, these clinical manifesta­tions of mitochondrial dysfunction mayaIso arise because of defects in nuclear genes. In contrast to mitochondrial genes,little is known about nuclear gene defects that interrupt mitochondrial function.

It is estimated that of the 4 million children born each year in the United States, up to 4000 are born with mitochondrial diseases. To date, the molecular mechanisms responsible for mtDNA mutations and mi­tochondrial dysfunction remain unsolved, so it is timely to survey the current status of the field. This book is intended to serve as a source of information about mtDNA mutations and mitochondrial dysfunction relevant to aging, disease and cancer. I am confident that this book will be helpful to investigators working in such diverse fields as molecular biology, cell biology, genetics, pharmacology, toxicology, medicine, neu­robiology, aging and cancer, and will promote rapid advances in under­standing the underlying mechanisms of mitochondrial diseases.

This book is organized into two broad sections. In the first sec­tion, the authors review the most recent data on the basic principles of mitochondrial biology. In the second section, defects leading to abnor­mal mitochondrial metabolism important in aging, disease and cancer are discussed. This book also provides up-to-date information on the modeling of mtDNA mutations and potential gene therapies for treat­ment of mitochondrial diseases.

Keshav K. Singh Spring 1998

CONTENTS

1. Introduction ................................................................................... 1

Dongchon Kang, Koichiro Takeshige, Mutsuo Sekiguchi and Keshav K. Singh

Mitochondria Are Essential for Energy Dependent Function of the Cell ................................................................. 1

Discovery of Mitochondrial DNA and Mitochondrial Diseases ................................................... 1

Oxidative Stress: A Common Factor in Aging, Disease and Cancer ................................................................. 2

Mitochondrial DNA Mutations and Aging ............................... 8 Mitochondrial DNA Mutations and Diseases .......................... 9 Mitochondria and Cancer ........................................................ 10

Therapy of Mitochondrial Diseases ......................................... 11

Conclusions ................................................................................ 11

2. Mitochondrial Structure, Function and Biogenesis ............... 17 Alfred S. Lewin Introduction ................................................................................ 17 Mitochondrial Structure ........................................................... 18 Mitochondrial Function ........................................................... 23 Mitochondrial Biogenesis ......................................................... 28 Future Prospects ................................................................ : ....... 33

3. The Mitochondrial Genetic System ........................................... 43 Howard T. Iacobs and Ian I. Holt Introduction ............................................................................... 43 The Mitochondrial Genome ..................................................... 43 Maintenance of Mitochondrial DN A ....................................... 51 Mitochondrial Assembly and the MGS ................................... 67 Signaling and Integration in Mitochondrial Biogenesis ....... 69 Conclusions ................................................................................ 71

4. Inheritance ofMitochondrial Mutations ................................. 85 C. William Birky, Ir. Why We Need to Understand the Inheritance

and Population Genetics of Mitochondria .......................... 85 Intracellular Population of Mitochondrial Genes .................. 85 Maternal Inheritance ................................................................ 87 Random Drift of Gene Frequencies ......................................... 87 Evidence for Relaxed Replication and Partitioning ............... 90 A Simple Mathematical Model of the Inheritance

ofNeutral Mitochondrial Mutations ................................... 91 Non-Neutral Mitochondrial Genetics ..................................... 93 Data and Theory Needed to Improve Our Understanding

ofHuman Mitochondrial Genetics ...................................... 96

5. Mitochondrial DNA Replication ............................................. 101 Kylie F. Keshav and Shonen Yoshida Introduction .............................................................................. 101 H-Strand Synthesis .................................................................. 102 L-Strand Synthesis .................................................................. 105 Enzymes Involved in Mitochondrial DNA Replication ....... 106 Inhibitors of Mitochondrial DNA Replication ..................... 108 Future Trends .......................................................................... 109

6. Genetic Integrity of the Mitochondrial Genome .................... 115 Lene Juel Rasmussen and Keshav K. Singh Introduction .............................................................................. 115 Factors Contributing to Mitochondrial

Genome Instability ............................................................... 115 Consequences of Mitochondrial Genome Instability ........... 116 Types of DNA Repair ............................................................... 118 DNA Repair in Mitochondria ................................................. 121 Conelusions .............................................................................. 122

7. Modeling Mitochondrial DNA Mutations ............................. 129 T.B.L. Kirkwood and A. Kowald Why Model Mitochondrial Mutations? ................................. 129 Modeling mtDNA Mutations ................................................. 130 "Defective Organelle" Model .................................................. 131 "Network Theory" of Aging .................................................... 134 Mitochondrial DNA Damage and Cancer .............................. 139 Mitochondrial Mutations in Plants ....................................... 140 Conelusion ............................................................................... 142

8. Mitochondrial Regulation of Apoptosis ................................ 147 Patrice X. Petit and Guido Kroemer Introduction .............................................................................. 147 Alterations of Mitochondrial Functions

as Early Event of Apoptosis ................................................ 148 Modulation of Mitochondrial Permeability Transition

Decides Cell Fate ................................................................... 153 Bel-2 as an Endogenous Regulator

of Permeability Transition .................................................. 156 Bel-XL (Bcl-2) and Hypothetical Pore Regulation ................ 157 Conclusions and Prospects ..................................................... 158

9. Characteristics ofMitochondrial DNA Diseases .................. 167 Carlos T. Moraes Introduction ............................................................................. 167 mtDNA Rearrangements ........................................................ 167 Point Mutations of mtDNA .................................................... 170 Alterations of mtDNA Associated

with Mendelian Inheritance ................................................ 175 Clinical Considerations .......................................................... 176

10. Nuclear Defects Affecting Mitochondrial Function ............. 185

Brian H. Robinson Introduction .............................................................................. 185 Principles of Energy Metabolism ............................................ 185 Pro tein Composition of the Mitochondrial

Respiratory Chain ................................................................ 186 Symptoms Typical of Defects in Energy Metabolism .......... 186 Defects Located in Mitochondrial DNA ................................. 187 Mutations in Pro tein Co ding mtDNA Sequences ................ 188 Mutations in RNA Co ding Sequences ................................... 189 Defects Encoded in the Nucleus ............................................ 190 Differential Diagnosis ofEnergy Metabolism Defects ........ 197

11. Mitochondrial DNA Mutations in Aging ............................... 205

Phillip Nagley and Chunfang Zhang Introduction ............................................................................. 205 Mutations in Human mtDNA During Aging ........................ 206 Mutations in mtDNA ofOther Organisms ........................... 225 Possible Functional Consequences of Somatic mtDNA

Mutations in Aging .............................................................. 227 The Vicious Cirde Revisited .................................................. 230

12. Mitochondrial DNA Mutations and Heart Disease .............. 239 Takayuki Ozawa and Mika Hayakawa Introduction ............................................................................. 239 Point Mutational Genotype and Clinical Phenotype ........... 248

Somatic Mutations ................................................................... 253 Conclusion and Perspective ................................................... 256

13. Mitochondrial Dysfunction and Neurodegenerative Diseases ....................................................................................... 265 Michael Lin and M. Flint Beal Role ofMitochondria in General Mechanisms

of Cell Death ......................................................................... 265 Mitochondrial Involvement

in Specific Neurodegenerative Diseases ............................. 271

Conclusion ............................................................................... 278

14. Toxin Induced Mitochondrial Dysfunction and Neurodegeneration ............................................................ 297 Mohammad I. Sabri Introduction ............................................................................. 297 Mitochondrial Dysfunction

and Neurodegenerative Disorders ..................................... 300 Selected Environmental Toxins, Energy Dysfunction

and Neurodegeneration ...................................................... 300 Mitochondrial Dysfunction and Mechanisms

of Neurodegeneration ......................................................... 306

15. Perspectives on Mitochondria in Carcinogenesis ................. 319 Brian Bandy and Allan J. Davison Introduction .............................................................................. 319 Roles ofMitochondria in Neoplastic Transformation ......... 319 Mitochondria are Sensitive to Mutagens

and to Nongenotoxic Carcinogens .................................... 322 Mitochondrial Mutations

May Increase Oxidative Stress ............................................ 323 Mitochondrial DNA Segments

Are Found in Nuclear Genomes ......................................... 324 Oxidative Stress as a Common Factor in Aging,

Mitochondrial Injury and Carcinogenesis ......................... 325 Overview ofMitochondria and Oxidative Stress

in Transformation ................................................................ 325

16. The Mitochondrion as a Target for Cancer Chemotherapy ........................................................ 337 Josephine S. Modica-Napolitano Historical Perspective .............................................................. 337 Recent Research ...................................................................... 339 Directions for Future Research ............................................... 341

17· Prohibitin: Mitochondrial Tumor Suppressor Protein ....... 345 J. Keith McClung Introduction ............................................................................. 345 Evolutionary Conservation .................................................... 346 Cell Growth Regulation ........................................................... 351

Tumor Suppression .................................................................. 353 Functional Activity ofProhibitin 3'UTRs ............................. 356 Conclusions ............................................................................. 360

18. Abnormal Growth and Male Sterility Associated with Mitochondrial DNA Rearrangements in Plants ........... 365 Kathleen]. Newton and Susan]. Gabay-Laughnan Introduction ............................................................................. 365 Abnormal Growth Mutations ................................................ 367 Cytoplasmic Male Sterility ...................................................... 371

Concluding Remarks .............................................................. 376

19. Mitochondrial Disorder and Migraine ................................... 383 K.M.A. Welch and Charles Plippen Introduction ............................................................................. 383 Mechanisms of the Migraine Attack ..................................... 385 Brain Hyperexcitability Between Migraine Attacks ............. 386 Mitochondrial Disorder in Migraine ..................................... 386 Conclusion ................................................................................ 391

20. Gene Therapy of Mitochondrial DN A Diseases .................... 395 Peter Seibel, Adrian Flierl, Corinna Bachmann

and Martina Seibel Introduction ............................................................................. 395 Somatic Gene Therapy Approaches

for mtDNA Diseases ............................................................ 395 Conclusion .............................................................................. 400

Color Figures ........................................................................................ 403

Index ..................................................................................................... 409

ir====== EDITOR Keshav K. Singh

The Divisions of Experimental Therapeutics and Radiation Oncology

Johns Hopkins Oncology Center and

Department of Environmental Health Johns Hopkins School of Public Health

600 N. Wolfe Street, Room 2-121

Baltimore, Maryland, 21287 U.S.A. Chapters 1, 6

CONTRIBUTORS =====1 Corinna Bachmann Wissenschaftliche

Nachwuchsgruppe Biozentrum der Bayerischen

J ulius-Maximilians-Universität Wuerzburg, Germany Chapter 20

Brian Bandy Bioenergetics Research Laboratory Faculty of Applied Sciences Simon Fraser University Burnaby, British Columbia, Canada Chapter 15

M. Flint Beal N eurochemistry

and Neurology Service Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts, U.S.A. Chapter 13

C. William Birky, Jr. Department of Ecology

and Evolutionary Biology Graduate Interdisciplinary

Program in Genetics Biological Sciences West University of Arizona Tucson, Arizona, U.S.A. Chapter 4

Allan J. Davison Bioenergetics Research Laboratory Faculty of Applied Sciences Simon Fraser University Burnaby, British Columbia

and Chemistry Department University ofNorthern British

Columbia Prince George, British Columbia,

Canada Chapter 15

Adrian Flierl Wissenschaftliche

Nachwuchsgruppe Biozentrum der Bayerischen

J ulius-Maximilians-Universität Wuerzburg, Germany Chapter 20

Charles Flippen Headache Research Center Department ofNeurology Henry Ford Hospital and Health

Science Center Detroit, Michigan, U.S.A. Chapter 19

Susan J. Gabay-Laughnan Department of Plant Biology University ofIllinois Urbana, Illinois, U.S.A. Chapter 18

Mika Hayakawa Department of Biomedical

Chemistry Nagoya University

School of Medicine Showa-ku, Nagoya, Japan Chapter 12

Ian J. Holt Department of Molecular

and Cellular Pathology University of Dundee Ninewells Hospital Dundee, Scotland, U.K. Chapter 3

Howard T. Jacobs Institute of Medical Technology University ofTampere Tampere, Finland and Robertson Laboratory

of Biotechnology Institute of Biomedical

and Life Science University of Glasgow Glasgow, Scotland, U.K. Chapter 3

Dongchon Kang Department of Clinical Chemistry

and Laboratory Medicine Kyushu University

School of Medicine Fukuoka, Japan Chapter 1

Kylie F. Keshav Department of Bioscience

and Biotechnology Drexel University Philadelphia, Pennsylvania, U.S.A. Chapter 5

T.B.L. Kirkwood Collegium Budapest

(Institute for Advanced Study), Budapest, Hungary and Biological Gerontology Group Department of Geriatrie Medicine

and School of Biological Sciences University of Manchester Manchester, U.K. Chapter 7

A. Kowald Collegium Budapest

(Institute for Advanced Study), Budapest, Hungary and Department of Microbiology

and Genetics Technical University Berlin Berlin, Germany Chapter 7

Guido Kroemer Unite de Genetique Moleculaire

du Development Centre National de la Recherche

Scientifique Villejuif, France ChapterB

Alfred S. Lewin Department ofMolecular Genetics

and Medical Microbiology University ofFlorida College

ofMedicine Gainesville, Florida, U.S.A. Chapter 2

Michael Lin N eurochemistry

and N eurology Service Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts, U.S.A. Chapter 13

J. Keith McClung Department of Biology Radford University Radford, Virginia, U.S.A. Chapter 17

Josephine S. Modica-Napolitano Department of Biology Merrimack College North Andover, Massachusetts,

U.S.A Chapter 16

Carlos T. Moraes Departments ofNeurology

and of Cell Biology and Anatomy University of Miami School

ofMedicine Miami, Florida, U.S.A. Chapter 9

Phillip Nagley Department of Biochemistry

and Molecular Biology Monash University Clayton, Vietoria, Australia Chapter 11

Kathleen J. Newton Division of Biologieal Sciences University of Missouri Columbia, Missouri, U.S.A. Chapter 18

Takayuki Ozawa Department of Biomedieal

Chemistry Nagoya University

School of Medicine Showa-ku, Nagoya, Japan Chapter 12

Patrice X. Petit Unite de Genetique Moleculaire

du Development Centre National de la Recherche

Scientifique Villejuif, France Chapter 8

Lene Juel Rasmussen Department of Chemistry

and Life Sciences Roskilde University Roskilde, Denmark Chapter6

Brian H. Robinson Department of Pediatrics

and Biochemistry The University ofToronto

and Department of Genetics The Research Institute The Hospital for Siek Children Toronto, Ontario, Canada Chapter 10

Mohammed I. Sabri Center for Research

on Occupational and Environemental Toxicology

Oregon Health Sciences University Portland, Oregon, U.S.A. Chapter 14

Peter Seibel Wissenschaftliche

Nachwuchsgruppe Biozentrum der Bayerischen

J ulius-Maximilians-Universität Wuerzburg, Germany Chapter 20

Martina Seibel Wissenschaftliche

Nachwuchsgruppe Biozentrum der Bayerischen

J ulius-Maximilians-Universität Wuerzburg, Germany Chapter 20

Mutsuo Sekiguchi Department of Biology Fukuoka Dental College Fukuoka, Japan Chapter 1

Koichiro Takeshige Department of Biochemistry Kyushu University

School of Medicine Fukuoka, Japan Chapter 1

K.M.A. Welch Headache Research Center Department ofNeurology Henry Ford Hospital

and Health Science Center Detroit, Michigan, U.S.A. Chapter 19

Shonen Yoshida Laboratory of Cancer Cell Biology Research Institute for Disease

Mechanism and Control Nagoya University

School of Medicine Showa-ku, Nagoya, Japan Chapter 5

Chunfang Zhang Department of Biochemistry

and Molecular Biology Monash University Clayton, Victoria Australia Chapter 11