Mitochondria as a source of reactive oxygen species during reductive stress in rat hepatocytes

T. L. Dawson, G. J. Gores, A. L. Nieminen, B. Herman, J. J. Lemasters

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Abstract

Cell killing, oxygen consumption, and hydroperoxide formation were determined in rat hepatocytes after glycolytic and respiratory inhibition. These conditions model the ATP depletion and reductive stress of anoxia ('chemical hypoxia'). Glycolysis was inhibited with iodoacetate, and mitochondrial electron transfer was blocked with sodium azide, cyanide, or myxothiazol. Cell killing, hydroperoxide formation, and inhibitor-insensitive oxygen consumption were greater after azide than after myxothiazol or cyanide. Desferrioxamine, an inhibitor of iron-catalyzed hydroxyl radical formation, delayed cell killing after each of the respiratory inhibitors. Anoxia also delayed cell killing during chemical hypoxia. However, during anoxic incubations, desferrioxamine did not delay the onset of cell death. These findings indicate that reactive oxygen species participate in lethal cell injury during chemical hypoxia. In isolated mitochondria, previous studies have shown that myxothiazol inhibits Q cycle-mediated ubisemiquinone formation in complex III (ubiquinol-cytochrome c oxidoreductase) and that ubisemiquinone can react with molecular oxygen to form superoxide. Decreased killing of hepatocytes with myxothiazol compared with azide suggests, therefore, that mitochondrial oxygen radical formation by complex III is involved in cell killing during reductive stress. In support of this hypothesis, myxothiazol reduced rates of cell killing and hydroperoxide formation in hepatocytes incubated with azide or cyanide. This mitochondrial mechanism for oxygen radical formation may be important in relative but not absolute hypoxia.

Original languageEnglish (US)
Pages (from-to)C961-C967
JournalAmerican Journal of Physiology - Cell Physiology
Volume264
Issue number4 33-4
StatePublished - Jan 1 1993

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Keywords

  • Q cycle
  • cell killing
  • chemical hypoxia
  • cyanide
  • desferrioxamine
  • hydroperoxides
  • iodoacetate
  • myxothiazol
  • sodium azide

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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