title: Involvement of Ca2+ and ROS in alpha-tocopheryl succinate-induced mitochondrial permeabilization.
abstract: Release of mitochondrial proteins such as cytochrome c, AIF, Smac/Diablo etc., plays a crucial role in apoptosis induction. A redox-silent analog of vitamin E, alpha-tocopheryl succinate (alpha-TOS), was shown to stimulate cytochrome c release via production of reactive oxygen species (ROS) and Bax-mediated permeabilization of the outer mitochondrial membrane. Here we show that alpha-TOS facilitates mitochondrial permeability transition (MPT) in isolated rat liver mitochondria, Tet21N neuroblastoma cells and Jurkat T-lymphocytes. In particular, in addition to ROS production, alpha-TOS stimulates rapid Ca(2+) entry into the cells with subsequent accumulation of Ca(2+) in mitochondria-a prerequisite step for MPT induction. Alteration of mitochondrial Ca(2+) buffering capacity was observed as early as 8 hr after incubation with alpha-TOS, when no activation of Bax was yet detected. Ca(2+) accumulation in mitochondria was important for apoptosis progression, since inhibition of mitochondrial Ca(2+) uptake significantly mitigated the apoptotic response. Importantly, Ca(2+)-induced mitochondrial destabilization might cooperate with Bax-mediated mitochondrial outer membrane permeabilization to induce cytochrome c release from mitochondria.
authors.affiliation: Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. vladimir.gogvadze@ki.se
authors.forename: Vladimir
authors.initials: V
authors.lastname: Gogvadze
authors.forename: Erik
authors.initials: E
authors.lastname: Norberg
authors.forename: Sten
authors.initials: S
authors.lastname: Orrenius
authors.forename: Boris
authors.initials: B
authors.lastname: Zhivotovsky
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019169:Jurkat Cells; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D024508:Tocotrienols; D014810:Vitamin E / Q000031:analogs & derivatives; D024502:alpha-Tocopherol / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016877:Oxidants; D017382:Reactive Oxygen Species; D024508:Tocotrienols; D014810:Vitamin E; D045304:Cytochromes c; C082032:tocotrienol, alpha; D006861:Hydrogen Peroxide; D053148:Caspase 3; D024502:alpha-Tocopherol; D002118:Calcium