Journal Article

Complex II of the Mitochondrial Respiratory Chain Is the Key Mediator of Divalent Manganese-Induced Hydrogen Peroxide Production in Microglia

Yue Liu, David S. Barber, Ping Zhang and Bin Liu

in Toxicological Sciences

Volume 132, issue 2, pages 298-306
Published in print April 2013 | ISSN: 1096-6080
Published online January 2013 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfs344
Complex II of the Mitochondrial Respiratory Chain Is the Key Mediator of Divalent Manganese-Induced Hydrogen Peroxide Production in Microglia

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Exposure to excessive levels of manganese (Mn) is associated with the development of movement disorders, with symptoms overlapping with Parkinson’s disease. Oxidative damage has been implicated as a key contributor to Mn-induced neurotoxicity. We have recently reported that divalent Mn (Mn2+) stimulates brain microglia to produce and release hydrogen peroxide (H2O2), and microglial-free radical generation facilitates Mn2+-induced dopaminergic neurotoxicity. The goal of this study was to elucidate the underlying mechanism of the Mn2+-induced H2O2 production in microglia. Exposure to low micromolar concentrations of Mn2+, but not divalent copper, cadmium, nickel, cobalt, zinc, and iron, induced a significant production of H2O2 from rat microglial but not astroglial cells. Subcellular fractionation studies revealed that Mn2+ was capable of inducing significant H2O2 production in the mitochondrial but not the cytosolic or nuclear fraction prepared from microglia. Analysis of the relative contribution of mitochondrial respiratory chain complexes indicated that Mn2+-induced mitochondrial H2O2 production required the presence of complex II substrate succinate. In contrast, complex I substrates malate and glutamate failed to support H2O2 production in the presence of Mn2+. Furthermore, the succinate-supported Mn2+-induced mitochondrial H2O2 production was abolished by pharmacological inhibition of complex II but not that of complexes I and III, suggesting that mitochondrial complex II is a key mediator in Mn2+-induced H2O2 production. These findings advance our knowledge on the mechanisms by which Mn induces oxidative stress and the potential contribution to Mn neurotoxicity.

Keywords: heavy metal; reactive oxygen species; electron transport chain; neuroinflammation; glia.

Journal Article.  7315 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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