title: Complex II of the mitochondrial respiratory chain is the key mediator of divalent manganese-induced hydrogen peroxide production in microglia.
abstract: 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 (Mn(2+)) stimulates brain microglia to produce and release hydrogen peroxide (H2O2), and microglial-free radical generation facilitates Mn(2+)-induced dopaminergic neurotoxicity. The goal of this study was to elucidate the underlying mechanism of the Mn(2+)-induced H2O2 production in microglia. Exposure to low micromolar concentrations of Mn(2+), 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 Mn(2+) 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 Mn(2+)-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 Mn(2+). Furthermore, the succinate-supported Mn(2+)-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 Mn(2+)-induced H2O2 production. These findings advance our knowledge on the mechanisms by which Mn induces oxidative stress and the potential contribution to Mn neurotoxicity.
authors: Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA. liu@cop.ufl.edu
authors: Yue
authors: Y
authors: Liu
authors: David S
authors: DS
authors: Barber
authors: Ping
authors: P
authors: Zhang
authors: Bin
authors: B
authors: Liu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002413:Cations, Divalent; D004579:Electron Transport; D042963:Electron Transport Complex II / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008345:Manganese / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002413:Cations, Divalent; D017382:Reactive Oxygen Species; D008345:Manganese; D006861:Hydrogen Peroxide; D042963:Electron Transport Complex II