Skip to main content
SpringerLink
Log in

Mitochondrial myopathies: Disorders of the respiratory chain and oxidative phosphorylation

  • Disorders Of The Respiratory Chain And The Lactic Acidaemias
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Mitochondrial myopathies are a clinical condition characterized by muscle weakness and fatigue in which the primary defect is localized at the level of the mitochondria. Microscopic examination shows accumulations of mitochondria at the fibre periphery (ragged red fibres) and in some cases mitochondrial paracrystalline inclusions. The spectrum of different mitochondrial defects so far described is reviewed and data from cases investigated in this laboratory are described. The first case was a 17-year-old boy with a multisystem disorder whose muscle mitochondria showed low respiratory activity with all substrates, which doubled in the presence of uncouples Further investigation showed that the mitochondrial ATPase activity was only 6 % of normal. The next cases were a mother and daughter who showed a typical lipid storage myopathy. The latter was treated successfully with oral carnitine but the myopathy persisted. Mitochondrial investigations indicated a low respiratory activity with NAD-linked substrates but normal activity with succinate and ascorbate + TMPD. A defect in the NADH-CoQ reductase section of the respiratory chain was pinpointed possibly at an iron-sulphur centre. The fourth and fifth cases were two sisters who exhibited no lipid storage myopathy but whose mitochondrial activity was low with NAD-linked substrates but normal with succinate. Again a defect in the NADH-CoQ reductase (complex I) of the respiratory chain was determined. They were also investigated using31P-NMR. It was found after exercise that their muscle creatine phosphate levels took seven times longer to return to pre-exercise concentrations than control subjects.

These results are discussed with respect to the synthesis of mitochondrial proteins and the influence that both the mitochondrial and nuclear DNA have on this process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. M. L., Coulson, A. R., Drouin, J., Eperon, I. C., Mierlich, P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. M., Staden, P. and Young, I. G. S. Sequences and organisation of the human mitochondrial genome.Nature (London) 290 (1981) 457–465

    Article  CAS  Google Scholar 

  • Beinert, H. Iron sulphur centres of the mitochondrial electron transfer system — recent developments. In Lovenberg, W. (ed.)Iron-Sulfur Proteins, Vol. III, Academic Press, New York, 1977

    Google Scholar 

  • Birky, C. W., Acton, A. R., Dietrich, R. and Carver, M. Mitochondrial transmission genetics: replication, recombination and segregation of mitochondrial DNA and its inheritance crosses. In Slonimski, P., Borst, P. and Attardi, G. (eds.)Mitochondrial Genes, Cold Spring Harbor Laboratory, N.Y. (Symp. Quant. Biol), 1982, pp. 333–348

    Google Scholar 

  • Birky, C. W., Maruyama, T. and Fuerst, P. Population and evolutionary genetic theory for genes in mitochondria and chloroplasts.Genetics 103 (1983) 513–527

    PubMed  Google Scholar 

  • Blass, J. P., Avigon, J. and Uhlendorf, B. W. A defect in pyruvate decarboxylase in a child with an intermittent movement disorder.J. Clin. Invest. 49 (1970) 423–432

    Article  PubMed  CAS  Google Scholar 

  • Brown, G. G., Castora, F. J., Frantz, S. C. and Simpson, M. V. Mitochondrial DNA polymorphism: evolutionary studies on the genus Rattus.Ann. NY Acad. Sci. 361 (1981) 135–153

    Article  PubMed  CAS  Google Scholar 

  • Cerri, C. G., Meola, G. and Scarlato, G. Biochemical and morphological studies on a case of systemic carnitine deficiency.Acta Neuropathol. 7 (1981) 219–220

    CAS  Google Scholar 

  • Chapman, R. W., Stephens, J. C., Lansman, R. A. and Avise, J. C. Models of mitochondrial DNA transmission genetics and evolution in higher eucaryotes.Genet. Res. 40 (1982) 41–57

    Article  PubMed  CAS  Google Scholar 

  • Clark, J. B., Hayes, D. J., Byrne, E. and Morgan-Hughes, J. A. Mitochondrial myopathies — defects in mitochondrial metabolism in human skeletal muscle.Biochem. Soc. Trans. 11 (1983) 626–627

    PubMed  CAS  Google Scholar 

  • Daum, G., Bohni, P. C. and Schatz, G. Import of proteins into mitochondria. Cytochrome b2 and cytochrome c peroxides are located in the intermembrane space of yeast mitochondria.J. Biol. Chem. 257 (1982a) 13028–13033

    PubMed  CAS  Google Scholar 

  • Daum, G., Gasser, S. M. and Schatz, G. Import of proteins into mitochondria. Energy dependent, two step processing of the intermembrane space enzyme cytochrome b2 by isolated yeast mitochondria.J. Biol. Chem. 257 (1982b) 13075–13080

    PubMed  CAS  Google Scholar 

  • DiDonato, S., Castiglione, A., Rinold, M., Cornelio, F., Vendemia, F., Cardace, G. and Bertagnolio, B. Heterogeneity of carnitine palmitoyl transferase deficiency.J. Neurol. Sci. 50 (1981) 207–215

    Article  CAS  Google Scholar 

  • DiDonato, S., Cornelio, F., Pacini, L., Peluchetti, D. and Rimoldi, M. Muscle carnitine palmitoyl transferase deficiency. A case with enzyme deficiency in cultured fibroblasts.Ann. Neurol. 4 (1978) 465–467

    Article  PubMed  CAS  Google Scholar 

  • DiMauro, S. Metabolic myopathies. In Vinken, P. J.et al. (eds.)Handbook of Clinical Neurology, North Holland, Amsterdam, 1979, pp. 175–234

    Google Scholar 

  • DiMauro, S., Bonilla, E., Lee, C. P., Schotland, D. L., Scarpa, A., Conn, H. and Chance, B. Lufts disease: further biochemical and ultrastructural studies of skeletal muscle in the 2nd case.J. Neurol. Sci. 27 (1972) 217–232

    Article  Google Scholar 

  • DiMauro, S., Schotland, D. L., Bonilla, E., Lee, C. P., Gambetti, P. L. and Rowland, L. P. Progressive ophthalmoplegia, glycogen storage and abnormal mitochondria.Arch. Neurol. 29, (1973) 170–179

    PubMed  CAS  Google Scholar 

  • DiMauro, S., Mendell, J. R., Sahenk, Z., Bachman, D., Scarpa, A., Scofield, R. M. and Reiner, C. Fatal infantile mitochondrial myopathy and renal dysfunction due to cytochrome C oxidase deficiency.Neurology 30 (1980) 795–804

    PubMed  CAS  Google Scholar 

  • Engel, A. G. and Angelini, C. Carnitine deficiency of human skeletal muscle with associated lipid storage myopathy. A new syndrome.Science 179 (1973) 889–902

    Article  Google Scholar 

  • Fleischer, S. and Packer, L. (eds.) Biological oxidations. Mitochondrial and microbial systems.Meth. Enzymol. (1978) LIII

  • Gasser, S. M., Daum, G. and Schatz, G. Import of proteins into mitochondria. Energy-dependent uptake of precursors by isolated mitochondria.J. Biol. Chem. 257 (1982) 13034–13041

    PubMed  CAS  Google Scholar 

  • Giles, C., Blanc, H., Cann, H. M. and Wallace, D. C. Maternal inheritance of human mitochondrial DNA.Proc. Natl. Acad. Sci. USA 77 (1980) 6715–6719

    Article  PubMed  CAS  Google Scholar 

  • Grivell, L. A. Mitochondrial DNA.Sci. Am. 248 (1983) 60–73

    Article  Google Scholar 

  • Hanswirth, W. W. and Paipis, P. J. Rapid variation in mammalian mitochondrial genotypes: Implications for the mechanism of a maternal inheritance. In Slonimski, P., Borst, P. and Attardi, G. (eds.),Mitochondrial Genes, Cold Spring Harbor Laboratory, NY (Symp. Quant. Biol.), 1982, pp. 137–142

    Google Scholar 

  • Hayes, D. J., Summers, B. A., Morgan-Hughes, J. A. and Clark, J. B. A combined deficiency of muscle carnitine and mitochondrial ATPase activity in a patient with multisystem disease partially responsive to oral carnitine. InProceedings of the 5th International Congress on Neuromuscular Diseases, Marseilles, 1982, Abstr. 16.4

  • Heiman-Patterson, T. D., Bonilla, E., DiMauro, S., Foreman, J. and Schotland, D. L. Cytochrome c oxidase deficiency in a floppy infant.Neurology 32 (1982) 898–900

    PubMed  CAS  Google Scholar 

  • Hosking, G. P., Cavanagh, N. P. C., Smyth, D. P. L. and Wilson, J. Oral treatment of carnitine myopathy.Lancet 1 (1977) 853

    Article  PubMed  CAS  Google Scholar 

  • Howell, N. Origin, cellular expression and hybrid transmission of mitochondrial CAP-R, Pyr-INDr OLI-r mutant pheno-types.Somatic Cell Genet. 9 (1983) 1–24

    Article  PubMed  CAS  Google Scholar 

  • Kark, R. A. P. and Becte, D. M. Multiple genotypes, multiple phenotypes and partial defects.Muscle Nerve 4 (1981) 31–40

    Article  PubMed  CAS  Google Scholar 

  • Kark, R. A. P., Rodriguez-Budelli, M. and Blass, J. P. Evidence for a primary defect of lipoamide dehydrogenase in Friedreich’s ataxia.Adv. Neurol. 21 (1978) 163–180

    PubMed  CAS  Google Scholar 

  • Karpati, G., Carpenter, S., Engel, A., Watters, G., Allen, J., Rothman, S., Klassen, G. and Mamer, O. A. The syndrome of systemic carnitine deficiency.Neurology 25 (1975) 16–24

    PubMed  CAS  Google Scholar 

  • Land, J. M. and Clark, J. B. Mitochondrial myopathies.Biochem. Soc. Trans. 7 (1979) 231–245

    PubMed  CAS  Google Scholar 

  • Land, J. M., Morgan-Hughes, J. A. and Clark, J. B. Mitochondrial myopathy — biochemical studies revealing a deficiency of NADH-cytochrome b reduction activity.J. Neurol. Sci. 50 (1981) 1–13

    Article  PubMed  CAS  Google Scholar 

  • Lansman, R. A., Avise, J. C. and Huettel, M. D. Critical experimental test of the possibility of ‘paternal leakage’ of mitochondrial DNA.Proc. Natl. Acad. Sci. USA 80 (1983) 1969–1971

    Article  PubMed  CAS  Google Scholar 

  • Layzer, R. B., Havel, R. J. and Mcllroy, M. B. Partial deficiency of carnitine palmitoyl transferase: physiological and biochemical consequences.Neurology 30 (1980) 627–633

    PubMed  CAS  Google Scholar 

  • Lee, C. P., Sottocasa, E. L. and Ernster, L. Use of artificial electron acception for abbreviated phosphorylating electron transport: flavin cytochrome c.Meth. Enzymol. X (1967) 33–37

    Article  Google Scholar 

  • Luft, R., Ikkos, D., Palmieri, G., Ernster, L. and Afzelius, B. A case of severe hypermetabolism of non-thyroid origin with a defect in the maintenance of respiratory control: a correlated clinical, biochemical and morphological study.J. Clin. Invest. 41 (1962) 1776–1804

    Article  PubMed  CAS  Google Scholar 

  • Maccecchini, M. L., Ruhin, Y., Blobel, G. and Schatz, G. Import of proteins into mitochondria: precursor forms of the extra-mitochondrially made F1-ATPase subunits in yeast.Proc. Natl. Acad. Sci. USA 76 (1979) 343–347

    Article  PubMed  CAS  Google Scholar 

  • Makinen, M. W. and Lee, C. P. Biochemical studies of skeletal muscle mitochondria I. Microanalysis of cytochrome content, oxidative phosphorylative activities of mammalian skeletal muscle mitochondria.Arch. Biochem. Biophys. 126 (1968) 75–82

    Article  PubMed  CAS  Google Scholar 

  • Max, S. R., Garbus, J. and Wehman, H. J. Simple procedure for the rapid isolation of functionally intact mitochondria from human and rat skeletal muscle.Anal. Biochem. Sci. 46 (1972) 576–584

    Article  CAS  Google Scholar 

  • Morgan-Hughes, J. A. Defects of the energy pathways of skeletal muscle. In Matthews, W. B. and Glaser, G. H. (eds.)Recent Advances in Clinical Neurology, Churchill Livingstone, Edinburgh, 1982, pp. 1–46

    Google Scholar 

  • Morgan-Hughes, J. A. Disorders of mitochondrial metabolism; some clinical biochemical mechanisms. In Saunders, K. B. (ed.)Advanced Medicine 19, Pitman, London, 1983, pp. 243–260

    Google Scholar 

  • Morgan-Hughes, J. A., Darveniza, P., Kahn, S. M., Landon, D. N., Sherratt, R. M., Land, J. M. and Clark, J. B. A mitochondrial myopathy characterised by a deficiency in reducible cytochrome b.Brain 100 (1977) 617–640

    Article  PubMed  CAS  Google Scholar 

  • Morgan-Hughes, J. A., Darveniza, P., London, D. N., Land, J. M. and Clark, J. B. A mitochondrial myopathy with a deficiency of respiratory chain NADH-CoQ reductase activity.J. Neurol. Sci. 43 (1979) 27–46

    Article  PubMed  CAS  Google Scholar 

  • Morgan-Hughes, J. A., Hayes, D. J. and Clark, J. B. Mitochondrial myopathies. In Serratrice, G.et al. (eds.)Neuromuscular Diseases, 1984, Raven Press, New York, pp. 79–87

    Google Scholar 

  • Morgan-Hughes, J. A., Hayes, D. J., Clark, J. B., Landon, D. N., Swash, M., Stark, R. J. and Rudge, P. Mitochondrial encephalomyopathies. Biochemical studies in two cases revealing defects in the respiratory chain.Brain 105 (1982) 553–582

    Article  PubMed  Google Scholar 

  • Nobrega, F. G. and Tzagoloff, A. Assembly of mitochondrial membrane system complete restriction map of the cytochrome b region of mitochondrial DNA inS. cerevisiae.J. Biol. Chem. 255 (1980a) 9821–9827

    PubMed  CAS  Google Scholar 

  • Nobrega, F. G. and Tzagoloff, A. Assembly of mitochondrial membrane system: DNA sequence and organisation of the cytochrome b gene inS. cervisiae.J. Biol. Chem. 255 (1980b) 9828–9837

    PubMed  CAS  Google Scholar 

  • Ohashi, A., Gibson, J., Gregor, 1. and Schatz, G. Import of proteins into mitochondria. The precursor of cytochrome C1 is processed in two steps, one of them home dependent.J. Biol. Chem. 257 (1982) 13042–13047

    PubMed  CAS  Google Scholar 

  • Olson, W., Engel, W. K., Walsh, G. O. and Einaugler, R. Oculo cranio somatic neuromuscular disease with ‘ragged red’ fibres.Arch. Neurol. 26 (1972) 193–211

    PubMed  CAS  Google Scholar 

  • Prick, M., Gabreels, F., Renier, W., Trijbels, F., Jasper, H., Lamen, H. and Kok, J. Pyruvate dehydrogenase deficiency restricted to brain.Neurology 31 (1981) 227–230

    Google Scholar 

  • Radda, G. K., Bore, P. J., Gadian, G. D., Ross, B. D., Styles, P., Taylor, D. J. and Morgan-Hughes, J. A.31P NMR examination of 2 patients with NADH-CoQ reductase deficiency.Nature (London) 295 (1982) 608–609

    Article  CAS  Google Scholar 

  • Ragan, C. I. NADH-ubiquinone oxido reductase.Biochim. Biophys. Acta 456 (1976) 249–290

    PubMed  Google Scholar 

  • Reid, G. A. and Schatz, G. Import of proteins into mitochondria. Yeast cells grown in the presence of carbonyl cyanide m-chlorophenyl-hydrazone accumulate massive amounts of some mitochondrial precursor polypeptides.J. Biol. Chem. 257 (1982a) 13056–13061

    PubMed  CAS  Google Scholar 

  • Reid, G. A. and Schatz, G. Import of proteins into mitochondria. Extramitochondrial pools and post translational import of mitochondrial protein precursorsin vivo.J. Biol. Chem. 257 (1982b) 13062–13067

    PubMed  CAS  Google Scholar 

  • Reid, G. A., Yonetani, T. and Schatz, G. Import of proteins into mitochondria. Import and maturation of the mitochondrial intermembrane space enzymes cytochrome b2 and cytochrome c peroxidase in intact yeast cells.J. Biol. Chem. 257 (1982) 13068–13074

    PubMed  CAS  Google Scholar 

  • Robinson, B. H. and Sherwood, W. G. Pyruvate dehydrogenase phosphatase deficiency: a cause of congenital chronic lactic acidosis in infancy.Pediatr. Res. 9 (1975) 935–939

    Article  PubMed  CAS  Google Scholar 

  • Robinson, B. H., Taylor, J. and Sherwood, W. G. Deficiency of dihydrolipoyl dehydrogenase (a component of pyruvate and a ketoglutarate dehydrogenase complexes). A cause of congenital chronic lactic acidosis in infancy.Pediatr. Res. 11 (1977) 1198–1202

    PubMed  CAS  Google Scholar 

  • Schatz, G. How mitochondria import proteins from the cytoplasm.FEBS Lett. 103 (1979) 201–211

    Article  Google Scholar 

  • Schatz, G. and Mason, T. C. The biosynthesis of mitochondrial proteins.Annu. Rev. Biochem. 43 (1974) 51–87

    Article  CAS  Google Scholar 

  • Scholte, H. R., Busch, H. F. M. and Luft-Houwen, I. E. M. Functional disorders of mitochondria in muscle diseases -respiratory chain phosphorylation — the carnitine system. In Busch, H. F. M., Jennekens, G. G. J. and Scholte, H. R. (eds.)Mitochondria and Muscular Diseases, Mefar b.v., The Netherlands, 1981, pp. 133–145

    Google Scholar 

  • Schotland, D. L., DiMauro, S., Bonilla, F., Scarpa, A. and Lee, C. P. Neuromuscular disorder associated with a defect in mitochondrial energy supply.Arch. Neurol. 33 (1976) 475–479

    PubMed  CAS  Google Scholar 

  • Smyth, D. P. L., Lake, B. D., MacDermot, J. and Wilson, J. Inborn error of carnitine metabolism (carnitine deficiency) in man.Lancet 1 (1975) 1198–1199

    Article  PubMed  CAS  Google Scholar 

  • Solioz, M. and Schatz, G. Mutations in putative intervening sequences of the mitochondrial cytochrome b gene of yeast produce abnormal cytochrome b polypeptides.J. Biol. Chem. 254 (1979) 9331–9334

    PubMed  CAS  Google Scholar 

  • Spiro, A. J., Moore, C. L., Prineas, J. W., Strasberg, P. M. and Rapin, I. A cytochrome related inherited disorder of the nervous system and muscle.Arch. Neurol. 23 (1970) 103–112

    PubMed  CAS  Google Scholar 

  • Stansbie, D., Dormer, R. L. and Hughes, I. A. Mitochondrial myopathy with skeletal muscle cytochrome-c-oxidase deficiency.J. Inher. Metab. Dis. 5 (1982) 27

    Article  Google Scholar 

  • Suissa, M. and Schatz, G. Import of proteins into mitochondria. TranslatablemRNAs for imported mitochondrial proteins are present in free as well as mitochondria-bound cytoplasmic polysomes.J. Biol. Chem. 257 (1982) 13048–13055

    PubMed  CAS  Google Scholar 

  • Tzagoloff, A., Macino, G. and Sebalb, W. Mitochondrial genes and translation products.Annu. Rev. Biochem. 48 (1979) 419–441

    Article  PubMed  CAS  Google Scholar 

  • Van Biervliet, J. P. G. M., Bruinis, L., Ketting, D, de Bree, P. K., Van der Heiden, C., Wadman, S. K., Willems, J. L., Bookelman, H., Van Haelst, V. and Monnens, A. H. Hereditary mitochondrial myopathy with lactic acidaemia-a de Toni-Fanconi-Debré Syndrome and a defective respiratory chain in voluntary striated muscle.Pediatr. Res. 11 (1977) 1088–1090

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, University of London, St Bartholomew’s Hospital Medical College, Charterhouse Square, EC1M 6BQ, London, UK

    J. B. Clark & D. J. Hayes

  2. Department of Clinical Neurology, University of London, Institute of Neurology, Queen Square, WC1 3BG, London, UK

    D. J. Hayes, J. A. Morgan-Hughes & E. Byrne

Authors
  1. J. B. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. J. Hayes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. A. Morgan-Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Byrne
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This work was supported by the Brain Research Trust (DJ.H.) and the Muscular Dystrophy Group of Great Britain (J.M.H.) We also thank Dr G. K. Radda and his colleagues of Oxford University for the use of their NMR facilities. The electron micrograph was kindly provided by Dr D. N. Landon (Institute of Neurlogy, London).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clark, J.B., Hayes, D.J., Morgan-Hughes, J.A. et al. Mitochondrial myopathies: Disorders of the respiratory chain and oxidative phosphorylation. J. Inher. Metab. Dis. 7 (Suppl 1), 62–68 (1984). https://doi.org/10.1007/BF03047377

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03047377

Keywords

Search

Navigation