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

Eric L. Bell, Tatyana A. Klimova, James Eisenbart, Carlos T Moraes, Michael P. Murphy, G. R Scott Budinger, Navdeep S. Chandel

Research output: Contribution to journalArticle

333 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1029-1036
Number of pages8
JournalJournal of Cell Biology
Volume177
Issue number6
DOIs
StatePublished - Jun 18 2007

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Hypoxia-Inducible Factor 1
Electron Transport Complex III
Reactive Oxygen Species
Proteins
Hydroxylation
Cytochromes b
Null Lymphocytes
RNA Interference
Hydrogen Peroxide
Signal Transduction
Antioxidants

ASJC Scopus subject areas

  • Cell Biology

Cite this

The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production. / Bell, Eric L.; Klimova, Tatyana A.; Eisenbart, James; Moraes, Carlos T; Murphy, Michael P.; Budinger, G. R Scott; Chandel, Navdeep S.

In: Journal of Cell Biology, Vol. 177, No. 6, 18.06.2007, p. 1029-1036.

Research output: Contribution to journalArticle

Bell, Eric L. ; Klimova, Tatyana A. ; Eisenbart, James ; Moraes, Carlos T ; Murphy, Michael P. ; Budinger, G. R Scott ; Chandel, Navdeep S. / The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production. In: Journal of Cell Biology. 2007 ; Vol. 177, No. 6. pp. 1029-1036.
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