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

2005; Cell Press; Volume: 1; Issue: 6 Linguagem: Inglês

10.1016/j.cmet.2005.05.003

1932-7420

Kyle D. Mansfield, Robert D. Guzy, Yi Pan, Regina M. Young, Timothy P. Cash, Paul T. Schumacker, M. Celeste Simon,

High Altitude and Hypoxia

While cellular responses to low oxygen (O2) or hypoxia have been studied extensively, the precise identity of mammalian cellular O2 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 O2 sensing and subsequent HIF-1α and HIF-2α stabilization at 1.5% O2. In the absence of this signal, HIF-α subunits continue to be degraded. Furthermore, exogenous treatment with H2O2 or severe O2 deprivation is sufficient to stabilize HIF-α 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-1α and HIF-2α in this O2-sensing pathway.