The effect of nitric oxide on cell respiration:: A key to understanding its role in cell survival or death

The mitochondrion is a key organelle in the control of cell death. Nitric oxide (NO) inhibits complex IV in the respiratory chain and is reported to possess both proapoptotic and antiapoptotic actions. We investigated the effects of continuous inhibition of respiration by NO on mitochondrial energy status and cell viability. Serum-deprived human T cell leukemia (Jurkat) cells were exposed to NO at a concentration that caused continuous and complete (similar to 85%) inhibition of respiration. Serum deprivation caused progressive loss of mitochondrial membrane potential (Delta psi (m)) and apoptotic cell death. In the presence of NO, Delta psi (m), was maintained compared to controls, and cells were protected from apoptosis. Similar results were obtained by using stauroporin as the apoptotic stimulus. As exposure of serum-deprived cells to NO progressed (>5 h), however, Delta psi (m), fell, correlating with the appearance of early apoptotic features and a decrease in cel viability. Glucose deprivation or iodoacetate treatment of cells in the presence of NO resulted in a collapse of Delta psi (m), demonstrating involvement of glycolytic ATP in its maintenance. Under these conditions cell viability also was decreased. Treatment with oligomycin and/or bongkrekic acid indicated that the maintenance of Delta psi (m), during exposure to NO is caused by reversal of the ATP synthase and other electrogenic pumps. Thus, blockade of complex IV by NO initiates a protective action in the mitochondrion to maintain Delta psi (m); this results in prevention of apoptosis. It is likely that during cellular stress involving increased generation of NO this compound will trigger a similar sequence of events, depending an its concentration and duration of release.