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First published online 30 September 2008
doi: 10.1242/jcs.034660

Journal of Cell Science 121, 3468-3475 (2008)
Published by The Company of Biologists 2008
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Research Article

Mitochondrial dysfunction and HIF1{alpha} stabilization in inflammation

Assegid Garedew and Salvador Moncada*

The Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK

* Author for correspondence (e-mail: s.moncada{at}ucl.ac.uk)

Accepted 8 July 2008

Activation of murine-derived J774.A1 macrophages with interferon {gamma} and lipopolysaccharide leads to a progressive mitochondrial defect characterized by inhibition of oxygen consumption and a decrease in the generation of ATP by oxidative phosphorylation. These changes are dependent on the generation of nitric oxide (NO) by an inducible NO synthase that becomes a significant consumer of oxygen. Furthermore, in these activated cells there is a biphasic stabilization of the hypoxia-inducible factor HIF1{alpha}, the second phase of which is also dependent on the presence of NO. The mitochondrial defect and stabilization of HIF1{alpha} synergize to activate glycolysis, which, at its maximum, generates quantities of ATP greater than those produced by non-activated cells. Nevertheless, the amount of ATP generated is not sufficient to fulfil the energy requirements of the activated cells, probably leading to a progressive energy deficit with the consequent inhibition of cell proliferation and death.

Key words: Nitric oxide, Mitochondria, HIF1{alpha}, Inflammation, Glycolysis, Oxidative phosphorylation


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© The Company of Biologists Ltd 2008