title: Manganese ions enhance mitochondrial H2O2emission from Krebs cycle oxidoreductases by inducing permeability transition.
abstract: Manganese-induced toxicity has been linked to mitochondrial dysfunction and an increased generation of reactive oxygen species (ROS). We could recently show in mechanistic studies that Mn2+ions induce hydrogen peroxide (H2O2) production from the ubiquinone binding site of mitochondrial complex II (IIQ) and generally enhance H2O2formation by accelerating the rate of superoxide dismutation. The present study with intact mitochondria reveals that manganese additionally enhances H2O2emission by inducing mitochondrial permeability transition (mPT). In mitochondria fed by NADH-generating substrates, the combination of Mn2+and different respiratory chain inhibitors led to a dynamically increasing H2O2emission which was sensitive to the mPT inhibitor cyclosporine A (CsA) as well as Ru-360, an inhibitor of the mitochondrial calcium uniporter (MCU). Under these conditions, flavin-containing enzymes of the mitochondrial matrix, e.g. the mitochondrial 2-oxoglutaratedehydrogenase (OGDH), were major sources of ROS. With succinate as substrate, Mn2+stimulated ROS production mainly at complex II, whereby the applied succinate concentration had a marked effect on the tendency for mPT. Also Ca2+increased the rate of H2O2emission by mPT, while no direct effect on ROS-production of complex II was observed. The present study reveals a complex scenario through which manganese affects mitochondrial H2O2emission: stimulating its production from distinct sites (e.g. site IIQ), accelerating superoxide dismutation and enhancing the emission via mPT which also leads to the loss of soluble components of the mitochondrial antioxidant systems and favors the ROS production from flavin-containing oxidoreductases of the Krebs cycle.
authors.affiliation: Department of Anesthesiology, Intensive-Care Medicine and Pain Therapy, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Bonke
authors.affiliation: Department of Anesthesiology, Intensive-Care Medicine and Pain Therapy, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Siebels
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Zwicker
authors.affiliation: Department of Anesthesiology, Intensive-Care Medicine and Pain Therapy, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany. Electronic address: Stefan.Droese@kgu.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Dröse
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D002122:Calcium Chloride / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology*; D002952:Citric Acid Cycle / Q000187:drug effects* / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology; D042963:Electron Transport Complex II / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D017895:Manganese Compounds / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D010088:Oxidoreductases / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017975:Ruthenium Compounds / Q000494:pharmacology; D019802:Succinic Acid / Q000378:metabolism / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014451:Ubiquinone / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D002712:Chlorides; D017895:Manganese Compounds; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C112020:Ru 360; D017975:Ruthenium Compounds; C034703:mitochondrial calcium uniporter; D013481:Superoxides; D014451:Ubiquinone; D016572:Cyclosporine; D019802:Succinic Acid; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D007655:Ketoglutarate Dehydrogenase Complex; D042963:Electron Transport Complex II; D002122:Calcium Chloride; C025340:manganese chloride
keywords: 2-oxoglutarate dehydrogenase (OGDH); Complex II (succinate:ubiquinone oxidoreductase); Manganese; Mitochondria; Mitochondrial permeability transition (mPT); Reactive oxygen species (ROS)