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Science 12 December 2003:
Vol. 302. no. 5652, pp. 1975 - 1978
DOI: 10.1126/science.1088805
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Reports

Redistribution of Intracellular Oxygen in Hypoxia by Nitric Oxide: Effect on HIF1{alpha}

Thilo Hagen,1 Cormac T. Taylor,2 Francis Lam,1 Salvador Moncada1*

Cells exposed to low oxygen concentrations respond by initiating defense mechanisms, including the stabilization of hypoxia-inducible factor (HIF) 1{alpha}, a transcription factor that upregulates genes such as those involved in glycolysis and angiogenesis. Nitric oxide and other inhibitors of mitochondrial respiration prevent the stabilization of HIF1{alpha} during hypoxia. In studies of cultured cells, we show that this effect is a result of an increase in prolyl hydroxylase–dependent degradation of HIF1{alpha}. With the use of Renilla luciferase to detect intracellular oxygen concentrations, we also demonstrate that, upon inhibition of mitochondrial respiration in hypoxia, oxygen is redistributed toward nonrespiratory oxygen-dependent targets such as prolyl hydroxylases so that they do not register hypoxia. Thus, the signaling consequences of hypoxia may be profoundly modified by nitric oxide.

1 Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
2 Conway Institute for Biomedical and Biochemical Research, University College Dublin 4, Belfield, Dublin, Ireland.

* To whom correspondence should be addressed. E-mail: s.moncada{at}ucl.ac.uk

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