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

2+ ) stimulates brain microglia to produce and release hydrogen peroxide (H 2 O 2 ), 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 H 2 O 2 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 H 2 O 2 from rat microglial but not astroglial cells. Subcellular fractionation studies revealed that Mn 2+ was capable of inducing significant H 2 O 2 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 H 2 O 2 production required the presence of complex II substrate succinate. In contrast, complex I substrates malate and glutamate failed to support H 2 O 2 production in the presence of Mn 2+ . Furthermore, the succinate-supported