The thiol-specific antioxidant enzyme prevents mitochondrial permeability transition. Evidence for the participation of reactive oxygen species in this mechanism.
Mitochondrial swelling and membrane protein thiol oxidation associated with mitochondrial permeability transition induced by Ca2+ and inorganic phosphate are inhibited in a dose-dependent manner either by catalase, the thiol-specific antioxidant enzyme (TSA), a protein recently demonstrated to present thiol peroxidase activity, or ebselen, a selenium-containing heterocycle which also possesses thiol peroxidase activity. This inhibition of mitochondrial permeability transition is due to the removal of mitochondrial-generated H2O2 which can easily diffuse to the extramitochondrial space. Whereas ebselen required the presence of reduced glutathione as a reductant to grant its protective effect, TSA was fully reduced by mitochondrial components. Decrease in the oxygen concentration of the reaction medium also inhibits mitochondrial permeabilization and membrane protein thiol oxidation, in a concentration-dependent manner. The results presented in this report confirm that mitochondrial permeability transition induced by Ca2+ and inorganic phosphate is reactive oxygen species-dependent. The possible importance of TSA as an intracellular antioxidant, avoiding the onset of mitochondrial permeability transition, is discussed in the text.
Kowaltowski
A J
AJ
Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, 13083-970 Campinas, São Paulo, Brazil.
Netto
L E
LE
Vercesi
A E
AE
D000975:Antioxidants / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects*; D054833:Isoindoles; D008928:Mitochondria / Q000378:metabolism*; D009363:Neoplasm Proteins; D016566:Organoselenium Compounds / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D010544:Peroxidases / Q000494:pharmacology*; D054464:Peroxiredoxins; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D009363:Neoplasm Proteins; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; C042986:ebselen; D006861:Hydrogen Peroxide; D010544:Peroxidases; D054464:Peroxiredoxins; D002374:Catalase