title: Mitochondrial superoxide radical formation is controlled by electron bifurcation to the high and low potential pathways.
abstract: The generation of oxygen radicals in biological systems and their sites of intracellular release have been subject of numerous studies in the last decades. Based on these studies mitochondria are considered to be the major source of intracellular oxygen radicals. Although this finding is more or less accepted, the mechanism of univalent oxygen reduction in mitochondria is still obscure. One of the most critical electron transfer steps in the respiratory chain is the electron bifurcation at the cytochrome bc1 complex. Recent studies with genetically mutated mitochondria have made it clear that electron bifurcation from ubiquinol to the cytochrome bc1 complex requires the free mobility of the head domain of the Rieske iron-sulfur protein. On the other hand, it has been long known that inhibition of electron bifurcation by antimycin A causes leakage of single electrons to dioxygen, which results in the release of superoxide radicals. These findings lead us to study whether hindrance of the interaction of ubiquinol with the cytochrome bc1 complex is the regulator of single electron diversion to oxygen. Hindrance of electron bifurcation was observed following alterations of the physical state of membrane phospholipids in which the cytochrome bc1 complex is inserted. Irrespective of whether the fluidity of the membrane lipids was elevated or decreased, electron flow rates to the Rieske iron-sulfur protein were drastically reduced. Concomitantly superoxide radicals were released from these mitochondria, strongly suggesting an effect on the mobility of the head domain of the Rieske iron-sulfur protein. This revealed the involvement of the ubiquinol cytochrome bc1 redox couple in mitochondrial superoxide formation. The regulator, which controls leakage of electrons to oxygen, appears to be the electron-branching activity of the cytochrome bc1 complex.
authors.affiliation: Institute of Pharmacology and Toxicology, Veterinary University Vienna, Austria.
authors.forename: Katrin
authors.initials: K
authors.lastname: Staniek
authors.forename: Lars
authors.initials: L
authors.lastname: Gille
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Kozlov
authors.forename: Hans
authors.initials: H
authors.lastname: Nohl
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D002417:Cattle; D002784:Cholesterol / Q000378:metabolism; D003573:Cytochrome b Group / Q000737:chemistry / Q000378:metabolism; D003575:Cytochromes c1 / Q000737:chemistry / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D004579:Electron Transport; D014450:Electron Transport Complex III; D004583:Electrons; D004883:Erucic Acids / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008929:Mitochondria, Heart / Q000502:physiology*; D009245:NADH Dehydrogenase; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013367:Submitochondrial Particles / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D003573:Cytochrome b Group; D004883:Erucic Acids; D007506:Iron-Sulfur Proteins; C049811:erucic acid; D013481:Superoxides; D014451:Ubiquinone; D000968:Antimycin A; D003575:Cytochromes c1; D002784:Cholesterol; D006861:Hydrogen Peroxide; D009245:NADH Dehydrogenase; D014450:Electron Transport Complex III; C003741:ubiquinol; D010100:Oxygen