Table Of ContentPATRICK LESTIENNE (Ed.)
Mitochondrial Diseases
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PATRICK LESTIENNE (Ed.)
Mitochondrial
Diseases
Models and Methods
With 75 Figures
Springer
Dr. PATRICK LESTIENNE
Directeur de Recherche INSERM
E 99-29 INSERM
Physiologie Mitochondriale
Universite Victor Segalen Bordeaux 2
146, rue Leo Saignat
33076 Bordeaux Cedex, France
[email protected]
The cover picture, taken by Barbara Stevens and Jane Sinclair, was donated by Bjorn
Afzelius. It symbolizes heteroplasmy, which is frequently encountered in mitochondrial
DNA diseases, suggesting their possible reversibility.
Library of Congress Cataloging-in-Publication Data
Mitochondrial diseases: models and methods I Patrick Lestienne (ed.). p. cm
Includes bibliographical references and index.
ISBN-13: 978-3-642-64166-4 e-ISBN-13: 978-3-642-59884-5
DOl: 10.1007/978-3-642-59884-5
I. Mitochondrial pathology-Molecular aspects. 2. Mitochondrial DNA. l. Lestienne,
Patrick.
RB147.5.M581999 616'.042-dc21 99-25405 CIP
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Foreword
For those like me who witnessed the beginning of the adventure of human mitochon
drial pathology, one can only be astounded by the extent and unexpectedness of what
the field has come to offer. Extent because nobody could have imagined the sheer size
of the domain. Unexpectedness because hitherto it was impossible to imagine the
clinical polymorphism that this pathology would represent.
The starting point was clear. Initially, there was the exceptional, and for a long time
unique, observation of euthyroidian hypermetabolism that Luft and colleagues
analyzed remarkably in biochemical and clinical terms. Thereafter, there was the
support provided by the electron microscopy studies of Afzelius, and the very first
visualization of mitochondrial abnormalities. That was way back in 1958. A few years
later, progress in the cytology and cytochemistry of skeletal muscle tissue was to
provide the means of detecting such abnormalities by examining sections with light
microscopy. The colorful term "ragged red fibers", coined by W.K. Engel, became uni
versally accepted, and this typical aspect with Gomori trichrome stain was to throw
light on the frequency with which these mitochondrial abnormalities could occur
under pathological conditions which, until then, had remained a total mystery regard
ing their mechanism: syndromes such as the ocular myopathies with their descending
evolution and the oculocraniosomatic syndromes. We were at the beginning of the
1970s.
At about the same time, biochemical analysis of mitochondria-enriched sub
cellular fractions was becoming applicable to human muscle specimens, provided
there was more material available than with a simple biopsy. The analysis of the
various respiratory chain complexes then paved the way for understanding this
pathology. Almost concomitantly, A. G. Engel and C. Angelini next demonstrated the
possible correction of abnormalities in long-chain fatty acid degradation by the admi
nistration of l-carnitine, a cofactor with a very simple structure. In that same year of
1973, Di Mauro showed how a deficiency in mitochondrial carnitine palmityl trans
ferase could result in certain lipidosis and paroxystic myoglobinurias.
A watershed was reached in the middle of the 1980s with the discovery of tools to
explore the mitochondrial genome, which was then sequenced. The first demonstra
tions of these gene alterations were made almost simultaneously in London by the
team headed by J. Morgan-Hughes and in Angers by P. Lestienne and G. Ponsot. This
heralded an explosion in studies on the mitochondrial cytopathies. It was already
known that double affection of the central nervous and muscle was frequent in this
pathology. The abbreviations MERRF and MELAS, coined by Di Mauro's team, then
came to designate syndromes in which there was both central nervous and muscle
VI Foreword
involvement. In this way, it became clear that Leigh's syndrome, Leber's disease, and a
range of cardiac, digestive, immune and endocrinal pathologies were all related to
mitochondrial abnormalities. Neonatal medicine moved forward with the discovery
of cytochrome oxidase deficiencies, which were frequently severe, sometimes benign
and regressive. Although this list is far from complete regarding the various aspects
involved in mitochondrial pathology, it is the schematic overview of the question as
seen through the eyes of one pathologist.
All this progress could never have been so rapid and dramatic without break
throughs in pure mitochondrial biology, especially the fine structure of mitochondrial
crests, the way the respiratory chain functions, the production of ATP, and the struc
ture and evolution of mitochondrial DNA. Without doubt, in the future we will need
to look not only at how all this progress in pure biology has had an impact on human
pathology, but also at the questions that these issues raise. This sort of symbiosis is to
be found in almost all sectors of neuromuscular pathology.
In my opinion, such collaboration between pathologists and biologists is one of the
keys to the vast progress which has been made in what is indeed a short period of
time. Regarding France, special mention should be given to the driving force repre
sented by the AFM and the 5-year INSERM network "Biologie Moleculaire et Patholo
gie des Mitochondries Humaines". Our thanks go to those who, with the inspiration
by Cecile Marsac and under the guidance of Patrick Lestienne, have collaborated on
this network. Most of the authors contributing to this volume have been associated
with this project. The result is testimony to the richness and depth of this network.
Their combined efforts represent a further step in the understanding of mitochon
drial biology, its dysfunctioning and the ways in which man may, in the near future,
be able to correct these serious pathological disorders.
MICHEL FARDEAU
Medical and Scientific Director
of the Institute of Myology
Salpetriere Hospital
Preface
The aim of this book is to gather several aspects of mitochondrial diseases put for
ward by various research teams who exchanged knowledge over the 5-year INSERM
network, "Biologie Moleculaire et Pathologie des Mitochondries Humaines". We hope
that this work will contribute to further progress in the understanding of the basic
aspects underlying human diseases.
I wish to express my thanks to the Association Fran,<aise pour la lutte contre les
Myopathies (AFM), the Institut National de la Recherche et de la Sante Medicale
(INSERM), the Ministere de l'Enseignement Superieur et de la Recherche, and the
Fondation pour la Recherche Medicale for their support.
Finally, I would like to acknowledge the contributing authors for accepting my invi
tation to collaborate on this project. Special thanks are extended to Drs. C. Godinot,
C. Marsac, J. P. Mazat and G. Ponsot for their advice, and the editorial team of Sprin
ger-Verlag for their help in the realization of this enterprise.
June 1999 PATRICK LESTIENNE
Contents
Introduction
P. LESTIENNE
1 Organization and Expression of the Mitochondrial Genome 5
J. VEZIERS and P. LESTIENNE
2 Mitochondrial DNA Inheritance in Mammals 18
D. CASANE and M. GUERIDE
3 Molecular Basis of Mitochondrial DNA Diseases . . . . . . . . . . .. 33
P. LESTIENNE, M. F. BOUZIDI, 1. DESGUERRE, and G. PONSOT
4 Structural Studies on Human Mitochondrial tRNAs . . . . . . . . . . . .. 59
C. FLORENTZ, H. BRuLE, M. HELM, and R. GIEGE
5 Structure, Function and Pathology of Complex I . . . . . . . . . . . . . . . . .. 73
H. DUBORJAL, R. BEUGNOT, V. PROCACCIO, J. P. ISSARTEL, and J. LUNARDI
6 Complex II or Succinate: Quinone Oxidoreductase and Pathology . . •. 87
P. LESTIENNE and C. DESNUELLE
7 The bcl Complex in the Mitochondrial Respiratory Chain ................ 97
G. BRASSEUR, P. BRIVET-CHEVILLOTTE, D. LEMESLE-MEUNIER, and J.-P. DI RAGO
8 Cytochrome c Oxidase and Mitochondrial Pathology 115
A. POYAU and C. GODINOT
9 ATPase-ATPsynthase and Mitochondrial Pathology ................... 129
K. BUCHET and C. GODINOT
10 Physiology and Pathophysiology of the Mitochondrial ADP/ATP Carrier ... 143
C. FIORE, V. TREZEGUET, C. SCHWIMMER, P. Roux, F. NOEL, A. C. DIANOUX,
G. J.-M. LAUQIN, G. BRAND OLIN, and P. V. VIGNAIS
11 The Normal and Pathological Structure, Function and Expression
of Mitochondrial Creatine Kinase .. . . . . . . . . . . . . . . . . ...... 159
E. CLOTTES, O. MARCILLAT, M. J. VACHERON, C. LEYDIER, and C. VIAL
x Contents
12 Pyruvate Dehydrogenase Deficiencies . . . . . . . . . . ... 173
C. MARSAC, D. FRAN«OIS, F. FOUQUE, and C. BENELLI
13 Electrochemical Gradient and Mitochondrial DNA in Living Cells . . . . . . . . . . . . 185
J. COPPEY, C. DURIEUX, and M. COPPEy-MOISAN
14 AH eteroplasmic Strain of O. subobscura.
An Animal Model of Mitochondrial Genome Rearrangement ............... 197
S. ALZIARI, N. PETIT, E. LEFAI, F. BEZIAT, P. LECHER, S. TOURAILLE, R. DEBISE,
and F. MOREL
15 Stability of the Mitochondrial Genome of Podospora anserina and Its Genetic Control 209
1. BELCOUR, A. SAINSARD-CHANET, C. JAMET-VIERNY, and M. PICARD
16 The Control of Ageing and Mitochondria ...... 229
P. LESTIENNE and J. VEZIERS
17 Roles of Mitochondria in Apoptosis .......................... 239
B. MIG NOTTE and G. KROEMER
18 The Triiodothyronine Mitochondrial Pathway ..................... 255
C. WRUTNIAK, P. ROCHARD, F. CASAS, and G. CABELLO
19 Cytoskeleton-Mitochondrial Interactions ............... 271
J.-F. LETERRIER and M. LINDEN
20 NADH Brain Determination by Micromeasurements of a Laser-Induced Fluorescence
in the Rat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
S. MOTTIN, P. LAPORTE, and R. CESPUGLIO
21 Allotopic Expression of Mitochondrial Genes: Further Steps in the Evolution
of Eukaryotic Cells and Therapeutic Strategy ............. . . . . . . 295
C. JACQ, M. CORRAL-DEBRINSKI, and S. HERMANN-LE DENMAT
22 Import of tRNA into Yeast Mitochondria: Experimental Approaches
and Possible Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
r. A. TARASSOV, N. S. ENTELIS, and R. P. MARTIN
23 The Import ofCytosolic tRNA into Plant Mitochondria . . . . . . . . . . . . . . . . . 317
1. MARECHAL-DROUARD, A. DIETRICH, A. MIREAU, N. PEETERS, and r. SMALL
24 Plant Cytoplasmic Male Sterility: AM itochondrial Pathology
and Its Biotechnological Application ............. . ...... 327
S. LITVAK, M. HERNOULD, E. ZABALETA, V. BLANC, D. BEGU, r. KUREK,
A. BREIMAN, X. JORDANA, A. MOURAS, and A. ARAYA
25 Histopathology of Skeletal Muscle Mitochondria ................ 343
N. B. ROMERO, M. COQUET, and H. CARRIER
Contents XI
26 Enzymatic and Polarographic Measurements of the Respiratory Chain Complexes 357
M. MALGAT, T. LETELLIER, G. DURRIEU, and J.-P. MAZAT
27 Mitochondrial DNA Analysis ......... . .............. 379
P. REYNIER, Y. MALTHIERY, and P. LESTIENNE
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
