Inhibition of mitochondrial complex IV leads to secondary loss complex II-III activity: implications for the pathogenesis and treatment of mitochondrial encephalomyopathies

Mitochondrion. 2007 Jul;7(4):284-7. doi: 10.1016/j.mito.2007.02.001. Epub 2007 Feb 12.


Mitochondrial encephalomyopathies, arising from deficiencies of the electron transport chain (ETC) give rise to a wide clinical spectrum of presentation and are often progressive in nature. The aetiology of mitochondrial encephalomyopathies have yet to be fully elucidated, however, a successive loss of ETC function may contribute to the progressive nature of these disorders. The possibility arises that as a consequence of a primary impairment of ETC activity, secondary damage to the ETC may occur. In order to investigate this hypothesis, we established a model of cytochrome oxidase (Complex IV) deficiency in cultured human astrocytoma 1321N cells. Potassium cyanide (KCN, 1mM) resulted in a sustained 50% (p<0.01) loss of complex IV. At 24h activities of the other ETC complexes were unaffected. However, at 72h significant loss of succinate-cytochrome c reductase (complex II-III) activity expressed as a ratio to the mitochondrial marker, citrate synthase was observed. (KCN treated; 0.065+/-0.011 vs controls; 0.118+/-0.017 mean+/-SEM, n=8, p<0.05). These results provide a possible mechanism for the progressive nature of ETC defects and why in some patients multiple patterns of ETC deficiencies can be demonstrated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytoma / metabolism
  • Cell Line
  • Citrate (si)-Synthase / metabolism
  • Coenzymes / metabolism
  • Electron Transport Complex II / metabolism*
  • Electron Transport Complex III / metabolism*
  • Electron Transport Complex IV / antagonists & inhibitors*
  • Electron Transport Complex IV / metabolism*
  • Glutathione / metabolism
  • Humans
  • Mitochondrial Encephalomyopathies / enzymology*
  • Mitochondrial Encephalomyopathies / pathology*
  • Mitochondrial Encephalomyopathies / therapy
  • Potassium Chloride / pharmacology
  • Protein Binding
  • Ubiquinone / analogs & derivatives
  • Ubiquinone / metabolism


  • Coenzymes
  • Ubiquinone
  • Potassium Chloride
  • Electron Transport Complex II
  • Electron Transport Complex IV
  • Citrate (si)-Synthase
  • Electron Transport Complex III
  • coenzyme Q10
  • Glutathione