Mitochondrial reactive oxygen species are required for hypoxic HIF alpha stabilization.
Multicellular organisms initiate adaptive responses when oxygen (O2) availability decreases. The underlying mechanisms of O2 sensing remain unclear. Mitochondria have been implicated in many hypoxia-inducible factor (HIF) -dependent and -independent hypoxic responses. However, the role of mitochondria in mammalian cellular O2 sensing has remained controversial, particularly regarding the use pharmacologic agents to effect hypoxic HIF alpha stabilization, which has produced conflicting data in the literature. Using murine embryonic cells lacking cytochrome c, we show that mitochondrial reactive O2 species (ROS) are essential for O2 sensing and subsequent HIF alpha stabilization at 1.5% O2. In the absence of this signal, HIF alpha subunits continue to be hydroxylated and degraded via the proteasome. Importantly, exogenous treatment with H2O2 and severe O2 deprivation is sufficient to stabilize HIF alpha even in the absence of functional mitochondrial. These results demonstrate that mitochondria function as O2 sensors and signal hypoxic HIF alpha stabilization by releasing ROS to the cytoplasm. The cytochrome c mutant embryonic cells provide a unique reagent to further dissect the role of mitochondria in O2 mediated-intracellular events.
Simon
M Celeste
MC
Howard Hughes Medical Institute, Dept. of Cell and Dev. Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA. celeste2@mail.med.upenn.edu
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D014158:Transcription, Genetic
D000975:Antioxidants; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen