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

We present evidence for a consumption of nitric oxide in mitochondrial membranes in the absence of substrate, in a nonsaturable process that is O2 dependent

S. Shiva; P. S. Brookes; R. P. Patel; P. G. Anderson; V. M. Darley-Usmar


Scholarcy highlights

  • I t has long been recognized that the interactions of nitric oxide with the mitochondrial respiratory chain may be important in mediating the biological effects of this signaling molecule
  • Three possibilities have been examined. At high O2 tensions, the consumption of NO in mitochondrial membranes is enhanced through an O2-dependent mechanism independent of electron transfer, and is competitive with cytochrome c oxidase inhibition. At low O2 tensions, the partitioning of NO into the inner membrane greatly enhances the potential of NO to modulate mitochondrial respiration. NO-dependent inhibition of respiration at low O2 tension may have a component that is caused by other NO-derived metabolites
  • It is evident that the reaction between NO and O2 in the mitochondrial membrane has a significant impact on the inhibition of cytochrome c oxidase and the consequent control of respiration
  • To determine whether NO is consumed by mitochondria in the absence of respiration, a series of 1 ␮M additions of NO were made to mitochondria, and the decay was monitored with the NO electrode
  • Known examples are the activation of soluble guanylate cyclase, interactions with hemoglobin, and as recently proposed, the inhibition of mitochondrial respiration
  • In the case of both soluble guanylate cyclase and cytochrome c oxidase, this finding is thought to be caused by a competition for NO between the ferrous heme and various NO-consuming pathways in the cell
  • The regulation of O2 and nitric oxide gradients by the controlled production of NO by enzymes at specific sites in the cell and the inhibition of respiration at cytochrome c oxidase represent a regulatory mechanism linking cell signaling to metabolism

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