FUNCTIONAL IMPLICATIONS OF NITRIC-OXIDE PRODUCED BY MITOCHONDRIA IN MITOCHONDRIAL METABOLISM

The effects of endogenous production of NO., catalysed by the mitochon drial nitric oxide synthase (NOS), on mitochondrial metabolism were st udied. The respiratory rates of intact mitochondria in State 4 were de creased by 40% and 28% with succinate and malate-glutamate, respective ly, in the presence of L-arginine (L-Arg); conversely, the O-2 uptake with N-G-methyl-L-arginine (NMMA), a competitive inhibitor of NOS, was increased. The production of NO. and the inhibition of the respirator y rates were dependent on the metabolic state in which mitochondria we re maintained: NO. production was probably supported by mitochondrial NADPH, the latter maintained by the energy-dependent transhydrogenase. In addition to the decline in the respiratory rate, an inhibition of ATP synthesis was also observed (40-50%) following supplementation wit h L-Arg. The dependence of the respiratory rates of mitochondria in St ate 3 and cytochrome oxidase activities on O-2 concentrations with eit her L-Arg or NMMA indicated that both processes were competitively inh ibited by NO. at the cytochrome oxidase level. This inhibition can be explained by the interaction of NO. with cytochrome oxidase at the bin uclear centre. The role of NO. as a physiological modulator of cytochr ome oxidase is discussed in terms of cellular metabolism.