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 (approximately 85%) inhibition of respiration. Serum deprivation caused progressive loss of mitochondrial membrane potential (Deltapsi(m)) and apoptotic cell death. In the presence of NO, Deltapsi(m) was maintained compared to controls, and cells were protected from apoptosis. Similar results were obtained by using staurosporin as the apoptotic stimulus. As exposure of serum-deprived cells to NO progressed (>5 h), however, Deltapsi(m) fell, correlating with the appearance of early apoptotic features and a decrease in cell viability. Glucose deprivation or iodoacetate treatment of cells in the presence of NO resulted in a collapse of Deltapsi(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 Deltapsi(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 Deltapsi(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 on its concentration and duration of release.
Beltrán
B
B
The Wolfson Institute for Biomedical Research, The Cruciform Building, University College London, Gower Street, London WC1E 6BT, United Kingdom.
Mathur
A
A
Duchen
M R
MR
Erusalimsky
J D
JD
Moncada
S
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free; D004734:Energy Metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D019169:Jurkat Cells; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology
D016895:Culture Media, Serum-Free; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D019311:Staurosporine