The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production

Journal of Cell Biology - Tập 177 Số 6 - Trang 1029-1036 - 2007
Eric L. Bell1, Tatyana A. Klimova1, James Eisenbart1, Carlos T. Moraes2, Michael P. Murphy3, G. R. Scott Budinger1, Navdeep S. Chandel1,4
11Department of Medicine,
23Department of Neurology and Cell Biology and Anatomy, School of Medicine, University of Miami, Miami, FL 33136
34Medical Research Council, Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge CB2 2XY, England, UK
42Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611

Tóm tắt

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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Journal of Cell Biology

Tập 177 Số 6

1029-1036

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