Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 2004K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bell, E. L. Articles by Chandel, N. S. Search for Related Content PubMed PubMed Citation Articles by Bell, E. L. Articles by Chandel, N. S. Related Collections Related Article Social Bookmarking                      What's this?

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 (HIF-1) protein. How cells transduce hypoxic signals to stabilize the HIF-1 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 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 Q_o site of complex III. These interventions maintained hydroxylation of HIF-1 protein and prevented stabilization of HIF-1 protein during hypoxia. Antioxidants maintained hydroxylation of HIF-1 protein and prevented stabilization of HIF-1 protein during hypoxia. Exogenous hydrogen peroxide under normoxia prevented hydroxylation of HIF-1 protein and stabilized HIF-1 protein. These results provide genetic and pharmacologic evidence that the Q_o site of complex III is required for the transduction of hypoxic signal by releasing ROS to stabilize the HIF-1 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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related Article

Hypoxic reaction to reactive oxygen

Nicole LeBrasseur
J. Cell Biol. 2007 177: 945a. [Full Text] [PDF]

This article has been cited by other articles:

• Chiu, H.-J., Fischman, D. A., Hammerling, U. (2008). Vitamin A depletion causes oxidative stress, mitochondrial dysfunction, and PARP-1-dependent energy deprivation. FASEB J. 22: 3878-3887 [Abstract] [Full Text]  
• Ader, I., Brizuela, L., Bouquerel, P., Malavaud, B., Cuvillier, O. (2008). Sphingosine Kinase 1: A New Modulator of Hypoxia Inducible Factor 1{alpha} during Hypoxia in Human Cancer Cells. Cancer Res. 68: 8635-8642 [Abstract] [Full Text]  
• Qutub, A. A., Popel, A. S. (2008). Reactive Oxygen Species Regulate Hypoxia-Inducible Factor 1{alpha} Differentially in Cancer and Ischemia. Mol. Cell. Biol. 28: 5106-5119 [Abstract] [Full Text]  
• Drose, S., Brandt, U. (2008). The Mechanism of Mitochondrial Superoxide Production by the Cytochrome bc1 Complex. J. Biol. Chem. 283: 21649-21654 [Abstract] [Full Text]  
• Brown, S. T., Nurse, C. A. (2008). Induction of HIF-2{alpha} is dependent on mitochondrial O2 consumption in an O2-sensitive adrenomedullary chromaffin cell line. Am. J. Physiol. Cell Physiol. 294: C1305-C1312 [Abstract] [Full Text]  
• Zhou, G., Dada, L. A., Chandel, N. S., Iwai, K., Lecuona, E., Ciechanover, A., Sznajder, J. I. (2008). Hypoxia-mediated Na-K-ATPase degradation requires von Hippel Lindau protein. FASEB J. 22: 1335-1342 [Abstract] [Full Text]  
• Yu, Y., Niapour, M., Zhang, Y., Berger, S. A. (2008). Mitochondrial regulation by c-Myc and hypoxia-inducible factor-1{alpha} controls sensitivity to econazole. Molecular Cancer Therapeutics 7: 483-491 [Abstract] [Full Text]  
• Guzy, R. D., Sharma, B., Bell, E., Chandel, N. S., Schumacker, P. T. (2008). Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis. Mol. Cell. Biol. 28: 718-731 [Abstract] [Full Text]  
• Lin, X., David, C. A., Donnelly, J. B., Michaelides, M., Chandel, N. S., Huang, X., Warrior, U., Weinberg, F., Tormos, K. V., Fesik, S. W., Shen, Y. (2008). A chemical genomics screen highlights the essential role of mitochondria in HIF-1 regulation. Proc. Natl. Acad. Sci. USA 105: 174-179 [Abstract] [Full Text]  
• Page, E. L., Chan, D. A., Giaccia, A. J., Levine, M., Richard, D. E. (2008). Hypoxia-inducible Factor-1{alpha} Stabilization in Nonhypoxic Conditions: Role of Oxidation and Intracellular Ascorbate Depletion. Mol. Biol. Cell 19: 86-94 [Abstract] [Full Text]  
• Hawkins, B. J., Solt, L. A., Chowdhury, I., Kazi, A. S., Abid, M. R., Aird, W. C., May, M. J., Foskett, J. K., Madesh, M. (2007). G Protein-Coupled Receptor Ca2+-Linked Mitochondrial Reactive Oxygen Species Are Essential for Endothelial/Leukocyte Adherence. Mol. Cell. Biol. 27: 7582-7593 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents