MODULATION OF THE MITOCHONDRIAL PERMEABILITY TRANSITION BY NITRIC-OXIDE

The influence of nitric oxide on mitochondrial permeability transition (MPT) phenomenon was studied. NO was generated by photolysis of S-nit roso-N-acetylcysteine, AcCys(NO), with green light (lambda = 550 nm). Two distinct effects of nitric oxide on rat Liver mitochondria were id entified. First, NO accelerated an onset of swelling in Ca2+-loaded mi tochondria in a cyclosporin-A-sensitive manner acting as an inducer of permeability transition. This was, apparently, a result of irreversib le alteration of mitochondrial function accompanying the inhibition of respiratory chain in the presence of calcium. Formation of ESR-visibl e iron-sulfur dinitrosyl complexes (g = 2.041) could also contribute t o the irreversible changes resulting in MPT induction. Second, NO chan ged significantly the response of mitochondria to Ca2+/phosphate-induc ed MPT, acting as a regulator of permeability transition. In this case the action of nitric oxide led to division of the mitochondria into t wo subpopulations: one which underwent the rapid permeability transiti on and another in which the MPT was inhibited. The effect of NO an Ca2 +/P-i-induced MPT was transient and resulted from reversible inhibitio n of cytochrome oxidase followed by the changes in transmembrane poten tial and Ca2+ distribution. The characteristic time of duration of the se NO modulated effects depended on nitric oxide as well as on oxygen concentrations. With increasing NO at fixed oxygen concentrations, thi s lime levelled off to reach a maximum value which was inversely relat ed to the oxygen concentration. It is concluded that under physiologic al condition the duration of reversible NO effects on mitochondrial fu nction could be determined by oxygen concentration.