Mitochondrial Reactive Oxygen Species are Required for Hypoxic HIFα Stabilization
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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 HIFα 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 HIFα stabilization at 1.5% O2. In the absence of this signal, HIFα subunits continue to be hydroxylated and degraded via the proteasome. Importantly, exogenous treatment with H2O2 and severe O2 deprivation is sufficient to stabilize HIFα even in the absence of functional mitochondrial. These results demonstrate that mitochondria function as O2 sensors and signal hypoxic HIFα 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.
Key Wordstranscription signal transduction HIF prolyl hydroxylases
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