title: Mitochondrial dysfunction and HIF1alpha stabilization in inflammation.
abstract: 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 HIF1alpha, the second phase of which is also dependent on the presence of NO. The mitochondrial defect and stabilization of HIF1alpha 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.
authors.affiliation: The Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Assegid
authors.initials: A
authors.lastname: Garedew
authors.forename: Salvador
authors.initials: S
authors.lastname: Moncada
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D006019:Glycolysis / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000502:physiology
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009569:Nitric Oxide; D000255:Adenosine Triphosphate