Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing |
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Authors: | Guzy Robert D Hoyos Beatrice Robin Emmanuel Chen Hong Liu Liping Mansfield Kyle D Simon M Celeste Hammerling Ulrich Schumacker Paul T |
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Affiliation: | Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA. |
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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-1 and HIF-2 and that an increase in reactive oxygen species (ROS) links this complex to HIF- stabilization. Using RNAi to suppress expression of the Rieske iron-sulfur protein of complex III, hypoxia-induced HIF-1 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-1 and HIF-2 stabilization by releasing ROS to the cytosol. |
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