title: Impact of endogenous nitric oxide on microglial cell energy metabolism and labile iron pool.
abstract: Microglial activation is common in several neurodegenerative disorders. In the present study, we used the murine BV-2 microglial cell line stimulated with gamma-interferon and lipopolysaccharide to gain new insights into the effects of endogenously produced NO on mitochondrial respiratory capacity, iron regulatory protein activity, and redox-active iron level. Using polarographic measurement of respiration of both intact and digitonin-permeabilized cells, and spectrophotometric determination of individual respiratory chain complex activity, we showed that in addition to the reversible inhibition of cytochrome-c oxidase, long-term endogenous NO production reduced complex-I and complex-II activities in an irreversible manner. As a consequence, the cellular ATP level was decreased in NO-producing cells, whereas ATPase activity was unaffected. We show that NO up-regulates RNA-binding of iron regulatory protein 1 in microglial cells, and strongly reduces the labile iron pool. Together these results point to a contribution of NO derived from inflammatory microglia to the misregulation of energy-producing reactions and iron metabolism, often associated with the pathogenesis of neurodegenerative disorders.
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Chénais
authors.forename: Hamid
authors.initials: H
authors.lastname: Morjani
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Drapier
mesh_terms: D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D004579:Electron Transport / Q000502:physiology; D042967:Electron Transport Complex I; D042963:Electron Transport Complex II; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D012313:RNA / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D003574:Cytochrome c Group; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D008070:Lipopolysaccharides; D009097:Multienzyme Complexes; D016601:RNA-Binding Proteins; D009569:Nitric Oxide; D012313:RNA; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D007501:Iron; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D000154:Aconitate Hydratase; D042967:Electron Transport Complex I