Mitochondria and hypoxic signaling: a new view.

Eukaryotic cells respond to low oxygen concentrations by upregulating hypoxic and downregulating aerobic nuclear genes (hypoxic signaling). Most of the oxygen-regulated genes in yeast require the mitochondrial respiratory chain for their up- or downregulation when cells experience hypoxia. Although it was shown previously that the mitochondrial respiratory chain is required for the upregulation of some hypoxic genes in both yeast and mammalian cells, its underlying role in this process has been unclear. Recently, we have reported that mitochondria produce nitric oxide (NO(*)) when oxygen becomes limiting. This NO(*) production is nitrite (NO(2) (-))-dependent, requires an electron donor, and is carried out by cytochrome c oxidase in a pH-dependent fashion. We call this activity Cco/NO(*) and incorporate it into a new model for hypoxic signaling. In addition, we have found that some of the NO(*) produced by Cco/NO(*) is released from cells, raising the possibility that mitochondrially generated NO(*) also functions in extracellular hypoxic signaling pathways.