Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1987 Oct;41(4):584–593.

Abnormal kinetic behavior of cytochrome oxidase in a case of Leigh disease.

M Glerum 1, B H Robinson 1, C Spratt 1, J Wilson 1, D Patrick 1
PMCID: PMC1684310  PMID: 2821802

Abstract

Cultured skin fibroblasts from a child with fatal lacticacidemia displayed an abnormally high lactate:pyruvate ratio of 77:1, compared with control values of 22:1-27:1. When protease-treated isolated mitochondria were used, activity of the respiratory-chain enzymes was found to be approximately 60% of normal, and adenosine triphosphate synthesis was found to be normal with all substrates tested. In mitochondria prepared by means of digitonin treatment, adenosine triphosphate synthesis was depressed with all substrates tested, suggesting a defect in the operation of the cytochrome oxidase complex. In disrupted whole cells from the patient, cytochrome oxidase activity was 56% of the activity in the control cell line with the lowest activity. In the presence of a twofold excess of oxidized cytochrome c, patient cells showed 31% of the activity in controls. Cytochrome oxidase activity in both sonicated whole-cell preparations and in sonicated mitochondria displayed abnormal kinetics with regard to the substrate-reduced cytochrome c, which was particularly evident in the presence of excess oxidized cytochrome c. We believe that kinetically abnormal cytochrome oxidase complex is responsible for the biochemical and clinical abnormalities present in this patient.

Full text

PDF
584

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. DiMauro S., Mendell J. R., Sahenk Z., Bachman D., Scarpa A., Scofield R. M., Reiner C. Fatal infantile mitochondrial myopathy and renal dysfunction due to cytochrome-c-oxidase deficiency. Neurology. 1980 Aug;30(8):795–804. doi: 10.1212/wnl.30.8.795. [DOI] [PubMed] [Google Scholar]
  2. DiMauro S., Nicholson J. F., Hays A. P., Eastwood A. B., Papadimitriou A., Koenigsberger R., DeVivo D. C. Benign infantile mitochondrial myopathy due to reversible cytochrome c oxidase deficiency. Ann Neurol. 1983 Aug;14(2):226–234. doi: 10.1002/ana.410140209. [DOI] [PubMed] [Google Scholar]
  3. Erecińska M., Wilson D. F. Regulation of cellular energy metabolism. J Membr Biol. 1982;70(1):1–14. doi: 10.1007/BF01871584. [DOI] [PubMed] [Google Scholar]
  4. Fischer J. C., Ruitenbeek W., Stadhouders A. M., Trijbels J. M., Sengers R. C., Janssen A. J., Veerkamp J. H. Investigation of mitochondrial metabolism in small human skeletal muscle biopsy specimens. Improvement of preparation procedure. Clin Chim Acta. 1985 Jan 15;145(1):89–99. doi: 10.1016/0009-8981(85)90022-1. [DOI] [PubMed] [Google Scholar]
  5. Groen A. K., Wanders R. J., Westerhoff H. V., van der Meer R., Tager J. M. Quantification of the contribution of various steps to the control of mitochondrial respiration. J Biol Chem. 1982 Mar 25;257(6):2754–2757. [PubMed] [Google Scholar]
  6. Heiman-Patterson T. D., Bonilla E., DiMauro S., Foreman J., Schotland D. L. Cytochrome-c-oxidase deficiency in a floppy infant. Neurology. 1982 Aug;32(8):898–901. doi: 10.1212/wnl.32.8.898. [DOI] [PubMed] [Google Scholar]
  7. Jacobus W. E., Moreadith R. W., Vandegaer K. M. Mitochondrial respiratory control. Evidence against the regulation of respiration by extramitochondrial phosphorylation potentials or by [ATP]/[ADP] ratios. J Biol Chem. 1982 Mar 10;257(5):2397–2402. [PubMed] [Google Scholar]
  8. Millis A. J., Pious D. A. Oxidative phosphorylation in mitochondria isolated from human fibroblasts. Biochim Biophys Acta. 1973 Jan 18;292(1):73–77. doi: 10.1016/0005-2728(73)90251-x. [DOI] [PubMed] [Google Scholar]
  9. Miyabayashi S., Narisawa K., Tada K., Sakai K., Kobayashi K., Kobayashi Y. Two siblings with cytochrome c oxidase deficiency. J Inherit Metab Dis. 1983;6(3):121–122. doi: 10.1007/BF01800742. [DOI] [PubMed] [Google Scholar]
  10. Monnens L., Gabreels F., Willems J. Letter: A metabolic myopathy associated with chronic lactic acidemia, growth failure, and nerve deafness. J Pediatr. 1975 Jun;86(6):983–983. doi: 10.1016/s0022-3476(75)80269-1. [DOI] [PubMed] [Google Scholar]
  11. Moreadith R. W., Batshaw M. L., Ohnishi T., Kerr D., Knox B., Jackson D., Hruban R., Olson J., Reynafarje B., Lehninger A. L. Deficiency of the iron-sulfur clusters of mitochondrial reduced nicotinamide-adenine dinucleotide-ubiquinone oxidoreductase (complex I) in an infant with congenital lactic acidosis. J Clin Invest. 1984 Sep;74(3):685–697. doi: 10.1172/JCI111484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Müller-Höcker J., Pongratz D., Deufel T., Trijbels J. M., Endres W., Hübner G. Fatal lipid storage myopathy with deficiency of cytochrome-c-oxidase and carnitine. A contribution to the combined cytochemical-finestructural identification of cytochrome-c-oxidase in longterm frozen muscle. Virchows Arch A Pathol Anat Histopathol. 1983;399(1):11–23. doi: 10.1007/BF00666215. [DOI] [PubMed] [Google Scholar]
  13. Robinson B. H., McKay N., Goodyer P., Lancaster G. Defective intramitochondrial NADH oxidation in skin fibroblasts from an infant with fatal neonatal lacticacidemia. Am J Hum Genet. 1985 Sep;37(5):938–946. [PMC free article] [PubMed] [Google Scholar]
  14. Robinson B. H., Taylor J., Sherwood W. G. The genetic heterogeneity of lactic acidosis: occurrence of recognizable inborn errors of metabolism in pediatric population with lactic acidosis. Pediatr Res. 1980 Aug;14(8):956–962. doi: 10.1203/00006450-198008000-00013. [DOI] [PubMed] [Google Scholar]
  15. Robinson B. H., Ward J., Goodyer P., Baudet A. Respiratory chain defects in the mitochondria of cultured skin fibroblasts from three patients with lacticacidemia. J Clin Invest. 1986 May;77(5):1422–1427. doi: 10.1172/JCI112453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Sengers R. C., Trijbels J. M., Bakkeren J. A., Ruitenbeek W., Fischer J. C., Janssen A. J., Stadhouders A. M., ter Laak H. J. Deficiency of cytochromes b and aa3 in muscle from a floppy infant with cytochrome oxidase deficiency. Eur J Pediatr. 1984 Jan;141(3):178–180. doi: 10.1007/BF00443221. [DOI] [PubMed] [Google Scholar]
  17. Sengers R. C., Trijbels J. M., Bakkeren J. A., Ruitenbeek W., Janssen A. J., Stadhouders A. M., ter Laak H. J. Demyelination and disturbed metabolism of pyruvate: a case report. Eur J Pediatr. 1983 Apr;140(2):127–130. doi: 10.1007/BF00441661. [DOI] [PubMed] [Google Scholar]
  18. Van Biervliet J. P., Bruinvis L., Ketting D., De Bree P. K., Van der Heiden C., Wadman S. K. Hereditary mitochondrial myopathy with lactic acidemia, a De Toni-Fanconi-Debré syndrome, and a defective respiratory chain in voluntary striated muscles. Pediatr Res. 1977 Oct;11(10 Pt 2):1088–1093. doi: 10.1203/00006450-197711100-00005. [DOI] [PubMed] [Google Scholar]
  19. Willems J. L., Monnens L. A., Trijbels J. M., Veerkamp J. H., Meyer A. E., van Dam K., van Haelst U. Leigh's encephalomyelopathy in a patient with cytochrome c oxidase deficiency in muscle tissue. Pediatrics. 1977 Dec;60(6):850–857. [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES