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

TitleThe Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production.
Publication TypeJournal Article
Year of Publication2007
AuthorsBell, EL, Klimova, TA, Eisenbart, J, Moraes, CT, Murphy, MP, Budinger, GRScott, Chandel, NS
JournalJ Cell Biol
Volume177
Issue6
Pagination1029-36
Date Published2007 Jun 18
ISSN0021-9525
KeywordsAnimals, Cell Hypoxia, Cytochromes b, Electron Transport Complex III, Hypoxia-Inducible Factor 1, alpha Subunit, Mitochondrial Proteins, Reactive Oxygen Species, Signal Transduction
Abstract

Mammalian cells increase transcription of genes for adaptation to hypoxia through the stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha) protein. How cells transduce hypoxic signals to stabilize the HIF-1alpha 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-1alpha 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-1alpha protein and prevented stabilization of HIF-1alpha protein during hypoxia. Antioxidants maintained hydroxylation of HIF-1alpha protein and prevented stabilization of HIF-1alpha protein during hypoxia. Exogenous hydrogen peroxide under normoxia prevented hydroxylation of HIF-1alpha protein and stabilized HIF-1alpha 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-1alpha protein.

DOI10.1083/jcb.200609074
Alternate JournalJ. Cell Biol.
Citation Key10.1083/jcb.200609074
PubMed ID17562787
PubMed Central IDPMC2064363
Grant List1P01HL071643-01A1000 / HL / NHLBI NIH HHS / United States
R01 CA123067 / CA / NCI NIH HHS / United States
MC_U105663142 / / Medical Research Council / United Kingdom
R01 GM060472 / GM / NIGMS NIH HHS / United States
CA123067-01 / CA / NCI NIH HHS / United States
GM60472-07 / GM / NIGMS NIH HHS / United States