title: Effect of auranofin on the mitochondrial generation of hydrogen peroxide. Role of thioredoxin reductase.
abstract: The mitochondrial production of hydrogen peroxide, in the presence of different respiratory substrates (succinate, glutamate, malate and isocitrate), is stimulated by submicromolar concentrations of auranofin, a highly specific inhibitor of thioredoxin reductase. This effect is particularly evident in the presence of antimycin. Auranofin was also able to unmask the production of hydrogen peroxide occurring in the presence of rotenone. However, at variance with whole mitochondria, auranofin does not stimulate hydrogen peroxide production in submitochondrial particles indicating that it does not alter the formation of hydrogen peroxide by the respiratory chain but prevents its removal. As the mitochondrial metabolism of hydrogen peroxide proceeds through the peroxidases linked to glutathione or thioredoxin, the relative efficiency of the two systems and the effects of auranofin were tested. In conclusion, the inhibition of thioredoxin reductase determines an increase of the basal flow of hydrogen peroxide leading to a more oxidized condition that alters the mitochondrial functions.
authors.affiliation: Dipartimento di Chimica Biologica, Università di Padova, Viale G. Colombo 3, 35121, Padova, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rigobello
authors.forename: Alessandra
authors.initials: A
authors.lastname: Folda
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Baldoin
authors.forename: Guido
authors.initials: G
authors.lastname: Scutari
authors.forename: Alberto
authors.initials: A
authors.lastname: Bindoli
mesh_terms: D000818:Animals; D001310:Auranofin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001310:Auranofin; D006861:Hydrogen Peroxide; D013880:Thioredoxin-Disulfide Reductase