Abstract-Cytochrome c oxidase (CcO; complex IV of the mitochondrial electron transport chain) is the primary site of cellular oxygen consumption and, as such, is central to oxidative phosphorylation and the generation of adenosinetriphosphate. Nitric oxide (NO), an endogenously-generated gas, modulates the activity of CcO. Depending on the intracellular oxygen concentration and the resultant dominant redox state of CcO, the interaction between CcO and NO can have a range of signaling consequences for cells in the perception of changes in oxygen concentration and the initiation of adaptive responses. At higher oxygen concentrations, when CcO is predominantly in an oxidized state, it consumes NO. At lower oxygen concentrations, when CcO is predominantly reduced, NO is not consumed and accumulates in the microenvironment, with implications for both the respiratory rate of cells and the local vascular tone. Changes in the availability of intracellular oxygen and in the generation of reactive oxygen species that accompany these interactions result in cell signaling and in regulation of oxygen-sensitive pathways that ultimately determine the nature of the cellular response to hypoxia. (Arterioscler Thromb Vasc Biol. 2010;30:643-647.)Key Words: nitric oxide Ⅲ reactive oxygen species Ⅲ cytochrome oxidase Ⅲ hypoxia Ⅲ mitochondria O xygen arose in the earth's atmosphere some 2.3 billion years ago as a by-product generated by photosynthesizing cyanobacteria in the oceans of the planet. 1 Hypotheses suggest that the accumulating presence of this colorless, odorless, but highly reactive molecule initially represented a major threat to life on earth. However, an endosymbiotic relationship that developed between 2 primitive cell types during this time led to the evolution of a unicellular organism which was not only resistant to the oxidizing properties of oxygen but could use them in the generation of energy through catalyzing the efficient oxidative metabolism of sugars, such as glucose, and fatty acids. 2,3 The key to this development was the incorporation of oxygen-consuming bacteria into the host cytoplasm, leading to the evolution of what have become mitochondria. Such was the increase in efficiency afforded by the use of oxygen as a substrate for the production of adenosine-triphosphate (ATP) that it enabled the rapid development of multicellular forms of life that were totally dependent on the utilization of this gas for some of their key metabolic processes. 4 It is not surprising, therefore, that during the course of evolution, molecular mechanisms have developed to respond to low oxygen concentrations [O 2 ] with the induction of a transcriptional response directed toward hypoxic adaptation. It has recently become clear that mitochondria play a critical role in determining the activation of this response.
Interaction Between Nitric Oxide and Cytochrome C OxidaseMitochondria produce ATP constantly and are therefore permanently active. The proton gradient that drives the ATP synthase (which generates the majority of ...