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Published online June 11, 2007
doi:10.1083/jcb.200609074
The Journal of Cell Biology, Vol. 177, No. 6, 1029-1036
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Bell et al.
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Article

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

Eric L. Bell1, Tatyana A. Klimova1, James Eisenbart1, Carlos T. Moraes3, Michael P. Murphy4, G.R. Scott Budinger1, and Navdeep S. Chandel1,2

1 Department of Medicine and 2 Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611
3 Department of Neurology and Cell Biology and Anatomy, School of Medicine, University of Miami, Miami, FL 33136
4 Medical Research Council, Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge CB2 2XY, England, UK

Correspondence to Navdeep S. Chandel: nav{at}northwestern.edu

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

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.


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