Proceedings of the National Academy of Sciences · 1998 · 850 citations · 32 references
Life SciencesBiochemistryPhysiologyEnzymologyMetabolic RegulationRedox BiochemistryCellular RespirationMitochondrial DysfunctionMitochondrial MetabolismMitochondrial PhysiologyReactive Oxygen SpeciesRespiration InhibitionIrreversible Enzyme InhibitionIrreversible InhibitionMitochondrial Respiration InhibitionMitochondrial Respiratory Chain InhibitionMitochondrial Respiratory Complex INitric OxideReduced GlutathioneRespiratory Chain Complexes
Both reversible and irreversible inhibition of mitochondrial respiration have been reported following the generation of nitric oxide (NO) by cells. Using J774 cells, we have studied the effect of long-term exposure to NO on different enzymes of the respiratory chain. Our results show that, although NO inhibits complex IV in a way that is always reversible, prolonged exposure to NO results in a gradual and persistent inhibition of complex I that is concomitant with a reduction in the intracellular concentration of reduced glutathione. This inhibition appears to result from S-nitrosylation of critical thiols in the enzyme complex because it can be immediately reversed by exposing the cells to high intensity light or by replenishment of intracellular reduced glutathione. Furthermore, decreasing the concentration of reduced glutathione accelerates the process of persistent inhibition. Our results suggest that, although NO may regulate cell respiration physiologically by its action on complex IV, long-term exposure to NO leads to persistent inhibition of complex I and potentially to cell pathology.
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Vascular endothelial cells synthesize nitric oxide from L-arginine
Richard Palmer, D. Ashton, Salvador Moncada · Nature · 1988 · 4.8K citations