| Abstract: |
Multicellular organisms initiate adaptive responses when oxygen (O2) availability decreases, but the underlying mechanism of O2 sensing remains elusive. We find that functionality of complex III of the mitochondrial electron transport chain (ETC) is required for the hypoxic stabilization of HIF-1α and HIF-2α and that an increase in reactive oxygen species (ROS) links this complex to HIF-α stabilization. Using RNAi to suppress expression of the Rieske iron-sulfur protein of complex III, hypoxia-induced HIF-1α stabilization is attenuated, and ROS production, measured using a novel ROS-sensitive FRET probe, is decreased. These results demonstrate that mitochondria function as O2 sensors and signal hypoxic HIF-1α and HIF-2α stabilization by releasing ROS to the cytosol. © 2005 Elsevier Inc. All rights reserved. |
| Keywords: |
signal transduction; controlled study; human cell; nonhuman; animal cell; mouse; metabolism; oxygen; basic helix-loop-helix transcription factors; protein binding; protein stability; transcription factor; enzymology; enzyme activity; cell line, tumor; transcription factors; hypoxia; transactivator protein; tumor cell line; fluorescence resonance energy transfer; reactive oxygen species; reactive oxygen metabolite; trans-activators; hydrogen peroxide; mitochondria; hypoxia inducible factor 1alpha; protein determination; mitochondrion; anoxia; cytosol; hif1a protein, human; hypoxia-inducible factor 1, alpha subunit; basic helix loop helix transcription factor; mitochondrial respiration; respiratory chain; oxygen sensing; oxygen concentration; hypoxia inducible factor 2alpha; ubiquinol cytochrome c reductase; hypoxia inducible factor 2, alpha subunit; hypoxia-inducible factor 2, alpha subunit; electron transport complex iii
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