Inhibition of cytochrome-c oxidase activity during prolonged hypoxia

N. Chandel, G. R S Budinger, R. A. Kemp, P. T. Schumacker*

*Corresponding author for this work

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79 Scopus citations

Abstract

During acute (< 30 min) hypoxia, cellular respiration is independent of the O2 concentration as long as PO2 remains above a critical value (5-10 Torr). Similarly, state 3 respiration by isolated mitochondria is independent of PO2 above a critical tension of 2-4 Torr. However, rat hepatocytes demonstrate a reversible suppression of respiration and an increase in NAD(P)H concentration during prolonged (2-24 h), but not acute hypoxia [P. T. Schumacker, N. Chandel, and A. G. N. Augusti. Am. J. Physiol. 265 (Lung Cell. Mol. Physiol. 9): L395-L402, 1993]. This study tested whether respiration is similarly inhibited in isolated mitochondria exposed to low PO2 for prolonged periods and whether cytochrome-c oxidase participates in this response. Coupled rat liver mitochondria were incubated under low oxygen conditions (PO2 < 2 Torr) for 2 h. State 3 respiration after reoxygenation to PO2 = 20 Torr was then compared with the value obtained subsequently at 100 Torr. Using succinate and ADP as substrates, we determined that state 3 respiration at 20 Torr was 61.0 ± 8.4% of the subsequent value at 100 Torr (P < 0.05). By contrast, control mitochondria reoxygenated to 100 Torr first and 20 Torr subsequently showed no significant difference at the two O2 tensions (P = NS). When TMPD was used as substrate to supply electrons directly to cytochrome c, respiration at 20 Torr in mitochondria incubated at low PO2 for 2 h was 50.7 ± 6.0% of the value measured subsequently at 100 Torr. To further test the role of cytochrome-c oxidase in this response, isolated bovine heart enzyme was incubated at PO2 = 20 Torr for 4 h. In the presence of excess substrate, O2 consumption by the enzyme at PO2 = 20 Torr decreased progressively, reaching a turnover rate of 23.5 ± 1.3 s-1 compared with 40.7 ± 0.9 s-1 during reoxygenation to 100 Torr (P < 0.001) after 4 h. We conclude that electron transport in rat hepatocyte mitochondria is reversibly inhibited after prolonged exposure to low PO2. This inhibition appears to be mediated by a regulatory effect of molecular oxygen on the catalytic behavior of cytochrome-c oxidase. These findings provide a mechanistic explanation for the reversible decrease in respiration by intact hepatocytes during prolonged exposure to hypoxia.

Original languageEnglish (US)
Pages (from-to)L918-L925
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume268
Issue number6 12-6
DOIs
StatePublished - 1995

Keywords

  • adenosine 5'-triphosphate
  • ischemia
  • mitochondria
  • oxygen
  • respiration

ASJC Scopus subject areas

  • Physiology (medical)
  • Physiology
  • Pulmonary and Respiratory Medicine
  • Cell Biology

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