Detection of Mitochondrial Diseases

316 Pages·1997·10.119 MB·English

by  William Bank, Britton Chance (auth.), Frank Norbert Gellerich, Stephan Zierz (eds.)

DETECTION OF MITOCHONDRIAL DISEASES
Developments in Molecular and Cellular Biochemistry
Series Editor: Naranjan S. Dhalla, Ph.D., M.D. (Hon.), FACC
1. V.A. Najjar (ed.): Biological Effects of Glutamic Acid and Its Derivatives. 1981 ISBN 90-6193-841-4
2. V.A. Najjar (ed.): Immunologically Active Peptides. 1981 ISBN 90-6193-842-2
3. V.A. Najjar (ed.): Enzyme Induction and Modulation. 1983 ISBN 0-89838-583-0
4. V.A. Najjar and L. Lorand (eds.): Transglutaminase. 1984 ISBN 0-89838-593-8
5. G.J. van der Vusse (ed.): Lipid Metabolism in Normoxic and Ischemic Heart. 1989 ISBN 0-7923-0479-9
6. J.F.e. Glatz and G.J. van der Vusse (eds.): Cellular Fatty Acid-Binding Proteins. 1990
ISBN 0-7923-0896-4
7. H.E. Morgan (ed.): Molecular Mechanisms of Cellular Growth. 1991 ISBN 0-7923-1183-3
8. G.J. van der Vusse and H. Stam (eds.): Lipid Metabolism in the Healthy and Diseased Heart. 1992
ISBN 0-7923-1850-1
9. Y. Yazaki and S. Mochizuki (eds.): Cellular Function and Metabolism. 1993 ISBN 0-7923-2158-8
10. J.F.C. Glatz and G.J. van der Vusse (eds.): Cellular Fatty-Acid-Binding Proteins, II. 1993
ISBN 0-7923-2395-5
11. R.L. Khandelwal and J.H. Wang (eds.): Reversible Protein Phosphorylation in Cell Regulation. 1993
ISBN 0-7923-2637-7
12. J. Moss and P. Zahradka (eds.): ADP-Ribosylation: Metabolic Effects and Regulatory Functions. 1994
ISBN 0-7923-2951-1
13. V.A. Saks and R. Ventura-Clapier (eds.): Cellular Bioenergetics: Role of Coupled Creatine Kinases. 1994
ISBN 0-7923-2952-X
14. J. Slezak and A. ZiegelhOffer (eds.): Cellular Interactions in Cardiac Pathophysiology. 1995
ISBN 0-7923-3573-2
15. J.A. Barnes, H.G. Coore, A.H. Mohammed and R.K. Sharma (eds.): Signal Transduction Mechanisms.
1995 ISBN 0-7923-3663-1
16. A.K. Srivastava and J.-L. Chiasson (eds.): Vanadium Compounds: Biochemical and Therapeutic Applica-
tions. 1995 ISBN 0-7923-3763-8
17. J.M.J. Lamers and P.D. Verdouw (eds.): Biochemistry of Signal Transduction in Myocardium. 1996
ISBN 0-7923-4067-1
18. E.-G. Krause and R. Vetter (eds.): Biochemical Mechanisms in Heart Function. 1996
ISBN 0-7923-4118-X
19. R. Vetter and E.-G. Krause (eds.): Biochemical Regulation ofM yocardium. 1996 ISBN 0-7923-4259-3
20. G.N. Pierce and W.C. Claycomb (eds.): Novel Methods in Molecular and Cellular Biochemistry of Muscle.
1997 ISBN 0-7923-4387-5
21. F.N. Gellerich and S. Zierz (eds.): Detection ofM itochondrial Diseases. 1997 ISBN 0-7923-9925-0
KLUWER ACADEMIC PUBLISHERS - DORDRECHT / BOSTON / LONDON
Detection of
Mitochondrial Diseases
Editedby
FRANK NORBERT GELLERICH
Martin Luther Universität Halle-Wittenberg
Neurologische Klinik und Poliklinik
Halle I Saale
Germany
and
STEPHAN ZIERZ
Martin Luther Universität Halle-Wittenberg
Neurologische Klinik und Poliklinik
Halle I Saale
Germany
Reprinted from Molecular and Cellular Biochemistry, Volume 174 (1997)
Springer-Science+Business Media, B.V.
A C.I.P. Catalogue record is available from the Library ofCongress
ISBN 978-1-4613-7800-6 ISBN 978-1-4615-6111-8 (eBook)
DOI 10.1007/978-1-4615-6111-8
Printed on acid-free paper
All rights reserved
@1997 Springer Science+Business Media Dordrecht
Originally published by Kluwer Academic Publishers in 1997
Softcover reprint ofthe hardcover 1st edition 1997
No part of the material protected by this copyright notice may be reproduced
or utilized in any form or by any means, electronic or mechanical,
including photocopying, recording or by any information storage and
retrieval system, without written permission from the copyright owner.
Molecular and Cellular Biochemistry:
An International Journal for Chemical Biology in Health and Disease
CONTENTS VOLUME 174, September 1997
DETECTION OF MITOCHONDRIAL DISEASES
F.N. Gellerich and S. Zierz, guest editors
Preface 1-3
Part I: Noninvasive detection of mitochondrial function
W. Bank and B. Chance: Diagnosis of defects in oxidative musclemetabolism by non-invasive tissue oximetry 7-10
B. Barbiroli, S. Iotti and R. Lodi: In vivo assessment of human skeletal·muscle mitochondria respiration in health and disease 11-15
J.A.L. Jeneson, R.W. Wiseman and MJ. Kushmerick: Non-invasive quantitative 31p MRS assay of mitochondrial function in
skeletal muscle in situ 17-22
R.W. Wiseman and M.J. Kushmerick: Phosphorus metabolite distribution in skeletal muscle: Quantitative bioenergetics using
creatine analogs 23-28
GJ. Kemp, D.N. Manners, J.F. Clark, M.E. Bastin and G.K. Radda: A theoretical model of some spatial and temporal aspects
of the mitochondrion creatine kinase myofibril system in muscle 29-32
. F.A. van Dorsten, T. Reese, J.F. Gellerich, CJ.A. van Echteld, M.GJ. Nederhoff, H.-J. Muller, G. van Vliet and
K. Nicolay: Fluxes through cytosolic and mitochondrial creatine kinase, measured by P-31 NMR 33-42
F.D. Laterveer, K. Nicolay, F.N. Gellerich: Experimental evidence for dynamic compartmentation of ADP at the mitochondrial
periphery: Coupling of mitochondrial adenylate kinase and mitochondrial hexokinase with oxidative phosphorylation under
conditions mimicking the intracellular colloid osmotic pressure 43-51
Part II: Bioenergetic investigation of isolated mitochondria, skinned muscle fibers and cells
H.N. Rasmussen and U.F. Rasmussen: Small scale preparation of skeletal muscle mitochondria, criteria of integrity, and assays
with reference to tissue function 55-60
H.R. Scholte, Y. Yu, J.D. Ross, 1.1. Oosterkamp, A.M.C. Boonman, H.F.M. Busch: Rapid isolation of muscle and heart
mitochondria, the lability of oxidative phosphorylation and attempts to stabilize the process in vitro by taurine, carnitine and
other compounds 61-66
V. Mildaziene, R. Baniene, A. Marcinkeviciute, Z. Nauciene, A. Kalvenas and A. Zimkus: Tetraphenylphosphonium inhibits
oxidation of physiological substrates in heart mitochondria 67-70
W. Sperl, D. Skladal, E. Gnaiger, M. Wyss, U. Mayr, J. Hager and F.N. Gellerich: High resolution respirometry of permeabilized
skeletal muscle fibers in the diagnosis of neuromuscular disorders 71-78
L. Kay, A. Rossi and V. Saks: Detection of early ischemic damage by analysis of mitochondrial function in skinned fibers 79-85
A. Toleikis, D. Majiene, S. Trumbeckaite and A. Dagys: The effects of ischemia and experimental conditions on the respiration
rate of cardiac fibers 87-90
S.P. Bessman and C. Mohan: Insulin as a probe of mitochondrial metabolism in situ 91-96
W.S. Kunz, K. Winkler, A.V. Kuznetsov, H. Lins, E. Kirches and C.W. Wallesch: Detection of mitochondrial defects by laser
fluorimetry 97-100
D. Kohnke, M. Schramm and J. Daut: Oxidative phosphorylation in myocardial mitochondria 'in situ': A calorimetric study on
permeabilized cardiac muscle preparations 101-113
P. Rustin, D. Chretien, B. Parfait, A. Rotig and A. Munnich: Nicotinamide adenine dinucleotides permeate through mitochondrial
membranes in human Epstein-Barr virus-transformed lymphocytes 115-119
L. Bettendorff, G. Goessens and F.E. Sluse: Reversibility of thiamine deficiency-induced partial necrosis and mitochondrial
uncoupling by addition of thiamine to neuroblastoma cell suspensions 121-124
M. Lamer, J. JOckel, G. Schuster and C. Becker: Dihydroorotat-ubiquinone oxidoreductase links mitochondria in the biosynthesis
of pyrimidine nuc1eotides 125-129
B. Kadenbach, V. Frank, T. Rieger and J. Napiwotzki: Regulation of respiration and energy transduction in cytochrome c oxidase
isozymes by allosteric effectors 131-135
B. Korzeniewski: Thermodynamic regulation of cytochrome oxidase 137-141
J.-P. Mazat, T. Letellier, F. Bedes, M. Malgat, B. Korzeniewski, L.S. Jouaville and R. Morkuniene: Metabolic control analysis
and threshold effect in oxidative phosphorylation: Implications for mitochondrial pathologies 143-148
G. Durrieu, T. Letellier, J. Antoch, J.-M. Deshouillers, M. Malgat and J.-P. Mazat: Identification of mitochondrial deficiency
using principal component analysis 149-156
Part III: Mitochondrial transition pore, radicals and diseases
J.J. Lemasters, A.-L. Nieminen, T. Qian, L.C. Trost and B. Herman: The mitochondrial permeability transition in toxic, hypoxic
and reperfusion injury 159-165
A.P. Halestrap, c.P. Connern, E.J. Griffiths and P.M. Kerr: Cyclosporin A binding to mitochondrial cyclophilin inhibits the
permeability transition pore and protects hearts from ischaemiaireperfusion injury 167-172
J.B. Hoek, E. Walajtys-Rode and X. Wang: Hormonal stimulation, mitochondrial CaH accumulation, and the control of the
mitochondrial permeability transition in intact hepatocytes 173-179
L. Scorrano, A. NicoIli, E. Basso, V. Petronilli and P. Bernardi: Two modes of activation of the permeability transition pore:
The role of mitochondrial cyclophilin 181-184
P.X. Petit, N. Zarnzami, J.-L. Vayssiere, B. Mignotte, G. Kroemer and M. Castedo: Implication of mitochondria in apoptosis 185-188
G.C. Brown: Nitric oxide inhibition of cytochrome oxidase and mitochondrial respiration: Implications for inflammatory,
neurodegenerative and ischaemic pathologies 189-192
J.B. Schulz, R. T. Matthews, T. Klockgether, J. Dichgans and M. Flint Beal: The role of mitochondrial dysfunction and neuronal
nitric oxide in animal models of neurodegenerative diseases 193-197
W. Augustin, I. Wiswedel, H. Noack, T. Reinheckel and O. Reichelt: Role of endogenous and exogenous antioxidants in the
defence against functional damage and lipid peroxidation in rat liver mitochondria 199-205
Part IV: Mitochondrial genome and diseases
S. Hofmann, R. Bezold, M. Jaksch, P. Kaufhold, B. Obermaier-Kusser and K.-D. Gerbitz: Analysis of the mitochondrial DNA
from patients with Wolfram (DIDMOAD) syndrome 209-213
J.P. Masl!cci, E.A. Schon and M.P. King: Point mutations in the mitochondrial tRNAL ys gene: Implications for pathogenesis and
mechanism 215-219
T. Ferlin, G. Guironnet, M.-C. Barnoux, R. Dumoulin, G. Stepien and B. Mousson: Detection of mitochondrial DNA deletions
by a screening procedure using the polymerase chain reaction 221-225
J. Montoya, H.L. Garstka, A. Perez-Martos and R.J. Wiesner: Regulation of mitochondrial transcription by mitochondrial
transcription factor A 227-230
S. Zanssen, M. Molnar, 1.M. SchrOder and G. Buse: Multiple mitochondrial tRNALeu[UURj mutations associated with infantile
myopathy 231-236
P. Kaufmann, M. El-Schahawi and S. DiMauro: Carnitine palmitoyltransferase II deficiency: Diagnosis by molecular analysis
of blood 237-239
Part V: Ageing, mitochondria and diseases
FJ.M. Trijbels, W. Ruitenbeek, M. Huizing, U. Wendel, J.A.M. Smeitink and R.C.A. Sengers: Defects in the mitochondrial
energy metabolism outside the respiratory chain and the pyruvate dehydrogenase complex 243-247
M.W. Riepe and A.C. Ludolph: Chemical preconditioning: A cytoprotective strategy 249-254
I. Maurer and H.-J. Moller: Inhibition of complex I by neuroleptics in normal human brain cortex parallels the extrapyramidal
toxicity of neuroleptics 255-259
A. Dorner, K. Schulze, U. Rauch and H.-P. Schultheiss: Adenine nucleotide translocator in dilated cardiomyopathy: Pathophys
iological alterations in expression and function 261-269
T. Klopstock, M. Naumann, P. Seibel, B. Schalke, K. Reiners and H. Reichmann: Mitochondrial DNA mutations in multiple
symmetric lipomatosis 271-275
J.M. SchrOder and M. Molnar: Mitochondrial abnormalities and peripheral neuropathy in inflammatory myopathy, especially
inclusion body myositis 277-281
E. O'Gorman, T. Piendl, M. Milller, D. Brdiczka and T. Wallimann: Mitochondrial intermembrane inclusion bodies: The
common denominator between human mitochondrial myopathies and creatine depletion, due to impairment of cellular
energetics 283-289
K. Majamaa, H. Rusanen, A. Remes and I.E. Hassinen: Metabolic interventions against complex I deficiency in MELAS
syndrome 291-296
A. Lindner, E. Hofmann, M. Naumann, G. Becker and H. Reichmann: Clinical, morphological, biochemical, and neuroradio-
logical features of mitochondrial encephalomyopathies. Presentation of 19 patients 297-303
S. Papa and V.P. Skulachev: Reactive oxygen species, mitochondria, apoptosis and aging 305-319
D.J. Taylor, GJ. Kemp, C.H. Thompson and G.K. Radda: Ageing: Effects on oxidative function of skeletal muscle in vivo 321-324
EJ. Brierley, M.A. Johnson, O.F.W. James and D.M. Turnbull: Mitochondrial involvement in the ageing process. Facts and
controversies 325-328
G. Lenaz, C. Bovina, C. Castelluccio, R. Fato, G. Formiggini, M.L. Genova, M. Marchetti, M.M. Pich, F. Pallotti, G.P. Castelli
and G. Biagini: Mitochondrial Complex I defects in aging 329-333
Index to Volume 174 335-340
Molecular and Cellular Biochemistry 174: 1-3, 1997.
© 1997 Kluwer Academic Publishers.
Preface
As long as only qualitative methods are used in a al.). Besides the measurements of activities of bioener
branch ofs cience, this cannot rise to a higher state than getically relevant metabolites, P-fluxes can be measured,
the descriptive one. especially those of the creatine kinase. Since there are sev
S. Arrhenius (1915) eral isoenzymes with different intracellular localization, it is
In: Quantitative Laws in Biological Chemistry necessary to learn more about the contribution of e.g. mito
chondrial creatine kinase for the overall31P-NMR signal (van
In October 1995, the 1st Colloquium on Mitochondria and Dorsten et al.). The measurement of phosphorylation poten
Myopathies was organized in Halle/Saale by the editors of tials requires the knowledge of the ADP concentration which
this focused issue. The meeting took up what might be called is calculated, assuming the creatine kinase to be in equilib
an East German tradition: from 1976-1990 Andreas Schmidt rium. This calculation, however, needs information on the
organized 7 clinically orientated Colloquia on Myology in homogeneity of the cytosol and the mitochondrial periphery
Jena, and from 1974-1990 a series of 12 Colloquia on Mito (Wiseman et al., Kemp et at., Laterveer et al.). Whether or
chondria focused on basic research aspects was arranged by not concentration gradients have to be taken into account for
Wolfgang Kunz in Magdeburg. At those meetings, East Ger ADP transport from the place of cell work into the mitochon
many was a mediator between East European, West European dria and whether ADP diffuses by itself or by means of shut
and American scientists. In continuation of this tradition, tles, is at present under intensive discussion (Wisemanet at.,
scientists from more than 17 countries working on mitochon Kemp et at.). Even quantitative evidence for the existence of
dria as neurologists, biochemists, geneticists, or as physiolo rate dependent ADP gradients across the mitochondrial outer
gists came to Halle. The name of the colloquium indicated membrane has been presented (Laterveer et al.). Finally, this
the combination of both basic and clinical mitochondrial section includes a new noninvasive technique for detection of
research. mitochondrial defects by NIR-spectroscopy. First results in in
At present we observe an increasing number of reports on vestigation of patients with metabolic myopathies were pre
bioenergetic investigations of human tissues. Their main aim sented (Bank et at.).
is the diagnosis of mitochondrial diseases. Many recently The noninvasive methods are powerful techniques for the
developed new techniques and concepts are in use, from detection of the existence of bioenergetic defects. However,
noninvasive spectroscopic and imaging investigations of the they provide no information on the molecular basis of the
patient to techniques on the molecular level in biopsy probes, defect. Therefore, biochemical, histochemical and genomic
in isolated and in cultivated cells. The extraordinary impor investigations of biopsies are necessary. The most common
tance of mitochondria for human life in health and disease method for the detection of mitochondrial defects is the esti
has been accepted not only by 'mitochondriacs' but also by mation of single enzymes and of complexes of the respira
many clinical researchers. 34 years ago, the first case of a mi tory chain (Lenaz et al., Maurer et al., Majamaa et al.) in
tochondrial disease was discovered by Luft [1]. Since then homogenates prepared from frozen biopsy. This method is
the list of mitochondrially caused diseases has rapidly in highly sensitive and very efficient. However, mitochondria
creased. List of mutations published in every issue of the consist of several hundred enzymes and the amount of ma
Journal of Neuromuscular Science demonstrates the currently terial required for single enzyme measurements is not so
strong interest in this area. The general importance of mito small as generally assumed. In addition, there are enzymes
chondria for medicine is underlined by the use of the termi as translocators which can be measured in functional intact
nus Mitochondrial Medicine as title for a recent review [2]. mitochondria only.
The first chapter of this issue deals with noninvasive meth Investigation of mitochondrial function requires measure
ods for investigation of mitochondrial function in human tis ments in native biopsies and many efforts have been made in
sues. 31P-NMR-measurements in the muscle allow the load recent years to elaborate experimental protocols for this. The
dependent determination of cytoplasmic concentrations of main problem is that we have only small amounts of tissue at
ATP and creatine phosphate. There are well-defined protocols one's disposal. To overcome this problem the classical meth
allowing the assessment of mitochondrial function in the ods for isolation of mitochondria have been miniaturized
muscle of patients (Jeneson et ai., Barbiroli et al., Taylor et (Scholte et al., Rasmussen et al.) and the skinned fiber tech-
2
nique (Kay et at., Mazat et at., Kunz et al., Sperl et at., oxygen as a shield against many diseases. In a review Papa
Toleikis et al., Kohnke et al.) has been developed. The mini and Skulachev demonstrate, however, that elevated oxygen
aturization of instruments resulted in an increase of the sen is one of the most dangerous metabolic conditions for the cell,
sitivity, allowing profound measurements in small amounts causing increased formation of reactive oxygen species which
of material. One example is the high resolution respirometry increases peroxidation oflipids, proteins (Augustin et aZ.) and
using a computer coupled oxygraph (Sperl et al.) or custom especially mitochondrial DNA. Reversible opening of the pore
made small oxygraphs (Rasmussen et at.) with extraordinar could be an optimal part of physiological processes to adjust
ily small measuring chambers. Alternative detection systems intracellular oxygen concentration (Papa and Skulachev).
are in use as the calorimetry (Daut et at.), redox potential A further reactive radical is nitric oxide, which was found
measurements by laser fluorescence spectroscopy (Kunz et to be an important agent in inflammatory, ischaemic and
al.), low temperature spectroscopy (Rasmussen et al.) or the neurodegenerative pathologies (Brown, Schulz et at.). Since
measurement of the mitochondrial electrochemical proton NO reversibly inhibits the cytochrome c oxidase this enzyme
gradient (Mildaziene et al.). could be one important sensor for suppressing the mitochondrial
The use of cell cultures overcomes the problem of transi function. Therefore an increased knowledge on the regula
toriness of isolated mitochondria and fibers (Rustin et al., tion of cytochrome c oxidase (Kadenbach et al., Korzeniew
Bettendorf et al., Masucci et al.). ski) is necessary.
Several papers deal with acute impairment of mitochondrial Due to its small size the mitochondrial genome is com
function by decreased concentration of coenzymes (Bettendorf pletely known, coding for 13 mitochondrial proteins of the
et al., Majammaa et al.) by ischemia (Halestrapet al., Toleikis respiratory chain and 24 t-RNA. Innumerable mutations most
et al.), by medicaments (Maurer et at.). On the other hand it of them very specific, have been found correlating more or
seems to be possible to use very small amounts of mitochon less with neuromuscular and other important diseases (Zanssen
drial inhibitors for a chemical preconditioning (Riepe et al.) et al., Masucci et al., Hofmann et al.). Screening methods
as a cytoprotective strategy. Mitochondria also participate at have been developed (Ferlin et al.). Mutations of mtDNA
many important cellular functions. One of them is the synthe create an intracellular mixture of mutant and normal DNA
sis of metabolites as nucleotides which could be impaired by molecules (heteroplasmy) and the transcription of these
a disturbed mitochondrial function (Loffler et al.). different molecules has to be understood in more detail
A well-known phenomenon in mitochondrial medicine is (Montoya et al.). It was shown that the Wolfram-Syndrome
the threshold effect, i.e. which degree of pathological change (DIDMOAD), a special form of diabetes, is caused by spe
of a single step is necessary to cause altered function of the cific changes in the mitochondrial genome (Hofman et aZ.).
metabolic system. Using the metabolic control theory, we can That mitochondria could also be included in the pathogenesis
try to understand and quantify such pathological changes of other forms of diabetes is shown by Bessman et al., who
(Mazat et aZ.). In addition, metabolic control theory is use could demonstrate that insulin influences the channelling of
ful to find out sensitive single steps and metabolic conditions C and C3 of pyruvate into the citric cycle.
2
in mitochondrial metabolism which are sensitive for patho Specific differences in the properties of the mitochondrial
logical changes (Korzeniewski). In order to utilize all infor and the nuclear genome make the mt-DNA vulnerable for
mation which may be hidden in the data obtained for each oxidative stress. In addition, a steady increase of the percent
patient, computer programs have been developed for identi age of mutations has been observed with age. Therefore the
fication of mitochondrial deficiencies using principal com mitochondria seem to be involved in the aging process. How
ponent analysis (Durrieu et al.). ever, this process is far from being understood. Using very
One of the most spectacular recent developments in re different methods from 31P-NMR spectroscopy (Taylor et al.),
search on mitochondrial pathology is the discovery of the genomic analysis (Brierley et at.) to rotenone titrations of
mitochondrial transition pore (Lemasters et al., Halestrap et complex I of the respiratory chain (Lenaz et al.), indeed age
al., Hoek et al., Scorrano et at.). Very different signals can related changes in the mitochondrial function have been
induce an opening of the pore causing a swelling of mitochon found. Sometimes the correlation of age related changes to
dria and the collapse of gradients across the mitochondrial the age is pure. Interestingly, a better correlation was found
inner membrane. Obviously, an irreversible opening of this to the physical fitness of the probands (Brierley et al.).
pore is a key event in a cascade causing cell death or apoptosis In spite of much considerable progress in the detection of
(Petit et al.). There are several strategies to prevent the pore mitochondrial causes of diseases there are many patients with
opening. One of them is the addition of cyclosporin A impaired energy metabolism but without defined molecular
(Halestrap et al.). defects. Since the 13 mitochondrially coded proteins are all
There is still a wide-spread belief that high oxygen con constituents of the respiratory chain, this part of the mitochon
centration within cells is useful for an optimal cell function dria is usually intensively investigated in search of defects.
and there are therapeutic strategies using elevated or pure However, an increasing number of mitochondrial defects
3
could be detected in nuclear coded proteins as carnitine cused issue. We thank all authors for their patience and co
palmitoyl transferase (Kaufmann et at.), PDHC, porin, operation that have made it possible to have this unique col
(Trijbels et at.), AdN-translocator (Domer et at.). lection of papers representing the current knowledge on
A comparison of clinical, morphological and neuro detection of mitochondrial causes of diseases. We especially
radiological features demonstrates the current problems in thank Professor N.S. Dhalla for making possible to publish
finding the final diagnosis in patients with mitochondrial these contributions together in this focused issue and as a hard
encephalomyopathies (Lindner et at., Klopstock et at.). cover book.
The power of histological investigation is demonstrated by
the detection of mitochondrial abnormalities in inflammatory
References
myopathies, supporting the view that acute processes also
disturb mitochondrial functions (Schroder et at.).
The detection of mitochondrial inter membrane inclusion I. Luft R. Ikkos D, Palmieri G, Ernster L, Afzelius B: A case of severe
bodies in mitochondria of patients with mitochondrial diseases hypermetabolism of nonthyroid origin with a defect in the maintenance
of mitochondrial respiratory control: a correlated biochemical and
and in cells or tissues of models disturbing the creatine me
morphological study. J Clin Invest 412: 1776-1804,1962
tabolism offers a common nominator between mitochondrial
2. Luft R: The development of mitochondrial medicine. Proc Natl Acad
myopathy and creatine depletion (O'Gorman et at.). In ad Sci USA 91: 8731-8738,1994
dition, the reversibility of the formation of these inclusion
bodies gives hints for a possible creatine therapy of mito Frank Norbert Gellerich and Stephan Zierz
chondriopathies. A further hopeful example is the therapy by Martin-Luther-Universitat Halle-Wittenberg
nicotinamide in defects in complex I (Majamaa et at.). Neurologische Klinik und Poliklinik
The most important contributions of the 1st Colloquium on Muskellabor, Julius-Kiihn-Str. 7
Mitochondria and Myopathies are now published in this fo- D-06097 Halle/Saale, Germany
PART I
NONINVASIVE DETECTION OF MITOCHONDRIAL FUNCTION