Cytochrome c oxidase maintains mitochondrial respiration during partial inhibition by nitric oxide

Nitric oxide (NO), generated endogenously in NO-synthase-transfected cells, increases the reduction of mitochondrial cytochrome c oxidase (CcO) at O(2) concentrations ([O(2)]) above those at which it inhibits cell respiration. Thus, in cells respiring to anoxia, the addition of 2.5 mu M L-arginine at 70 mu M O(2) resulted in reduction of CcO and inhibition of respiration at [O(2)] of 64.0 +/- 0.8 and 24.8 +/- 0.8 mu M, respectively. This separation of the two effects of NO is related to electron turnover of the enzyme, because the addition of electron donors resulted in inhibition of respiration at progressively higher [O(2)], and to their eventual convergence. Our results indicate that partial inhibition of CcO by NO leads to an accumulation of reduced cytochrome c and, consequently, to an increase in electron flux through the enzyme population not inhibited by NO. Thus, respiration is maintained without compromising the bioenergetic status of the cell. We suggest that this is a physiological mechanism regulated by the flux of electrons in the mitochondria and by the changing ratio of O(2): NO, either during hypoxia or, as a consequence of increases in NO, as a result of cell stress.