Inhibition of cytochrome-c oxidase activity during prolonged hypoxia

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).(ABSTRACT TRUNCATED AT 250 WORDS)