Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-α activation

While cellular responses to low oxygen (O-2) or hypoxia have been studied extensively, the precise identity of mammalian cellular O-2 sensors remains controversial. Using murine embryonic cells lacking cytochrome c, and therefore mitochondrial activity, we show that mitochondrial reactive oxygen species (mtROS) are essential for proper O-2 sensing and subsequent HIF-1 alpha and HIF-2 alpha stabilization at 1.5% O-2. In the absence of this signal, HIF-alpha subunits continue to be degraded. Furthermore, exogenous treatment with H2O2 or severe 02 deprivation is sufficient to stabilize HIF-a even in the absence of cytochrome c and functional mitochondria. These results provide genetic evidence indicating that mtROS act upstream of prolyl hydroxylases in regulating HIF-1a and HIF-2a in this O-2-sensing pathway.