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- Title
The Q<sub>0</sub> site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production.
- Authors
Bell, Eric L.; Klimova, Tatyana A.; Eisenbart, James; Moraes, Carlos T.; Murphy, Michael P.; Budinger, G. R. Scott; Chandel, Navdeep S.
- Abstract
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.
- Subjects
GENETIC transcription; HYPOXEMIA; PROTEINS; CYTOCHROME b; IRON-sulfur proteins; REACTIVE oxygen species
- Publication
Journal of Cell Biology, 2007, Vol 177, Issue 6, p1029
- ISSN
0021-9525
- Publication type
Article
- DOI
10.1083/jcb.200609074