Abstract
Multicellular organisms initiate adaptive responses when oxygen (O(2)) availability decreases, but the underlying mechanism of O(2) 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 alpha and HIF-2 alpha and that an increase in reactive oxygen species (ROS) links this complex to HIF-alpha stabilization. Using RNAi to suppress expression of the Rieske iron-sulfur protein of complex III, hypoxia-induced HIF-1 alpha stabilization is attenuated, and ROS production, measured using a novel ROS-sensitive FRET probe, is decreased. These results demonstrate that mitochondria function as O(2) sensors and signal hypoxic HIF-1 alpha and HIF-2 alpha stabilization by releasing ROS to the cytosol.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Basic Helix-Loop-Helix Transcription Factors
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Cell Line, Tumor
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Electron Transport Complex III / metabolism*
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Humans
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Hydrogen Peroxide / metabolism
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Hypoxia / metabolism*
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Hypoxia-Inducible Factor 1, alpha Subunit
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Mitochondria / enzymology
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Mitochondria / metabolism*
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Oxygen / metabolism*
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Reactive Oxygen Species / metabolism*
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Trans-Activators / metabolism
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Transcription Factors / metabolism
Substances
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Basic Helix-Loop-Helix Transcription Factors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Reactive Oxygen Species
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Trans-Activators
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Transcription Factors
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endothelial PAS domain-containing protein 1
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Hydrogen Peroxide
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Electron Transport Complex III
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Oxygen