Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase

An emerging and important site of action for nitric oxide (NO) within cells is the mitochondrial inner membrane, where NO binds to and inhibits member s of the electron transport chain, complex III and cytochrome c oxidase. Al though it is known that inhibition of cytochrome c oxidase by NO is competi tive with O-2, the mechanisms that underlie this phenomenon remain unclear, and the impact of both NO and O-2 partitioning into biological membranes h as not been considered. These properties are particularly interesting becau se physiological O-2 tensions can vary widely, with NO having a greater inh ibitory effect at low O-2 tensions (< 20 muM). In this study, we present ev idence for a consumption of NO in mitochondrial membranes in the absence of substrate, in a nonsaturable process that is O-2 dependent. This consumpti on modulates inhibition of cytochrome c oxidase by NO and is enhanced by th e addition of exogenous membranes. From these data, it is evident that the partition of NO into mitochondrial membranes has a major impact on the abil ity of NO to control mitochondrial respiration. The implications of this co nclusion are discussed in the context of mitochondrial lipid:protein ratios and the importance of NO as a regulator of respiration in pathophysiology.