Mammalian cells increase transcription of genes for adaptation to hypoxia through the stabilization of hypoxia-inducible factor 1α (HIF-1α) protein. How cells transduce hypoxic signals to stabilize the HIF-1α protein remains unresolved. We demonstrate that cells deficient in the complex III subunit cytochrome b, which are respiratory incompetent, increase ROS levels and stabilize the HIF-1α protein during hypoxia. RNA interference of the complex III subunit Rieske iron sulfur protein in the cytochrome b–null cells and treatment of wild-type cells with stigmatellin abolished reactive oxygen species (ROS) generation at the Qo site of complex III. These interventions maintained hydroxylation of HIF-1α protein and prevented stabilization of HIF-1α protein during hypoxia. Antioxidants maintained hydroxylation of HIF-1α protein and prevented stabilization of HIF-1α protein during hypoxia. Exogenous hydrogen peroxide under normoxia prevented hydroxylation of HIF-1α protein and stabilized HIF-1α protein. These results provide genetic and pharmacologic evidence that the Qo site of complex III is required for the transduction of hypoxic signal by releasing ROS to stabilize the HIF-1α protein.
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18 June 2007
Article|
June 11 2007
The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production
Tatyana A. Klimova,
Tatyana A. Klimova
1Department of Medicine
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Carlos T. Moraes,
Carlos T. Moraes
3Department of Neurology and Cell Biology and Anatomy, School of Medicine, University of Miami, Miami, FL 33136
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Michael P. Murphy,
Michael P. Murphy
4Medical Research Council, Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge CB2 2XY, England, UK
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G.R. Scott Budinger,
G.R. Scott Budinger
1Department of Medicine
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Navdeep S. Chandel
Navdeep S. Chandel
1Department of Medicine
2Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611
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Eric L. Bell
1Department of Medicine
Tatyana A. Klimova
1Department of Medicine
James Eisenbart
1Department of Medicine
Carlos T. Moraes
3Department of Neurology and Cell Biology and Anatomy, School of Medicine, University of Miami, Miami, FL 33136
Michael P. Murphy
4Medical Research Council, Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge CB2 2XY, England, UK
G.R. Scott Budinger
1Department of Medicine
Navdeep S. Chandel
1Department of Medicine
2Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611
Correspondence to Navdeep S. Chandel: [email protected]
Abbreviations used in this paper: DMOG, dimethyloxalylglycine; HIF, hypoxia-inducible factor; PHD, prolyl hydroxylase enzyme; ROS, reactive oxygen species; shRNA, short hairpin RNA; TFAM, mitochondrial transcription factor A; TMPD, N,N,N′,N′-tetramethyl-p-phenylenediamine; WT, wild-type.
Received:
September 12 2006
Accepted:
May 15 2007
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2007
J Cell Biol (2007) 177 (6): 1029–1036.
Article history
Received:
September 12 2006
Accepted:
May 15 2007
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Citation
Eric L. Bell, Tatyana A. Klimova, James Eisenbart, Carlos T. Moraes, Michael P. Murphy, G.R. Scott Budinger, Navdeep S. Chandel; The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production . J Cell Biol 18 June 2007; 177 (6): 1029–1036. doi: https://doi.org/10.1083/jcb.200609074
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