Impact of endogenous nitric oxide on microglial cell energy metabolism and labile iron pool.
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.
Chénais
Benoît
B
Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette, France.
Morjani
Hamid
H
Drapier
Jean-Claude
JC
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
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