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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2311-2317. Prepublished online as a Blood First Edition Paper on June 9, 2005; DOI 10.1182/blood-2005-03-1138. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-03-1138v1 106/7/2311    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Doege, K. Articles by Metzen, E. Search for Related Content PubMed PubMed Citation Articles by Doege, K. Articles by Metzen, E. Related Collections Hematopoiesis and Stem Cells Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Inhibition of mitochondrial respiration elevates oxygen concentration but leaves regulation of hypoxia-inducible factor (HIF) intact Kathrin Doege, Sandra Heine, Inga Jensen, Wolfgang Jelkmann, and Eric Metzen From the Institute of Physiology, University of Lübeck, Germany. The transcription factor hypoxia-inducible factor-1 (HIF-1) is critical for erythropoietin and other factors involved in the adaptation of the organism to hypoxic stress. Conflicting results have been published regarding the role of the mitochondrial electron transport chain (ETC) in the regulation of HIF-1. We assessed cellular hypoxia by pimonidazole staining and blotting of the O2-labile HIF-1 -subunit in human osteosarcoma cell cultures (U2OS and 143B). In conventional, gas-impermeable cell culture dishes, ETC inhibitors had no effect on pimonidazole staining or HIF-1 abundance in a 20% O2 atmosphere; both parameters were undetectable. Pimonidazole staining and HIF activity were substantial in 0.1% O2 irrespective of ETC inhibition. At an intermediate oxygen concentration (3% O2) pimonidazole staining and HIF- expression were detectable but strongly reduced after ETC inhibition in conventional cell cultures. All effects of ETC inhibition on HIF-1 regulation were eliminated in gas-permeable dishes. As shown in a 143B subclone deficient in mitochondrial DNA (2060), genetic inactivation of the ETC led to similar responses with respect to HIF-1 regulation as ETC inhibitors. Our data demonstrate that reduction of oxygen consumption reduces the O2 gradient in conventional cell cultures, causing elevation of the cellular O2 concentration, which leads to degradation of HIF-. 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