Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha 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 H(2)O(2) or severe O(2) deprivation is sufficient to stabilize HIF-alpha 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-1 alpha and HIF-2 alpha in this O(2)-sensing pathway.
Mansfield
Kyle D
KD
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Guzy
Robert D
RD
Pan
Yi
Y
Young
Regina M
RM
Cash
Timothy P
TP
Schumacker
Paul T
PT
Simon
M Celeste
MC
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism*; D004261:DNA Replication / Q000502:physiology; D004272:DNA, Mitochondrial / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D045304:Cytochromes c; D004272:DNA, Mitochondrial; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D015534:Trans-Activators; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human