title: Quercetin can act either as an inhibitor or an inducer of the mitochondrial permeability transition pore: A demonstration of the ambivalent redox character of polyphenols.
abstract: The Ca(2+)- and oxidative stress-induced mitochondrial permeability transition (MPT) plays an important role in phenomena ranging from tissue damage upon infarction to muscle wasting in some forms of dystrophy. The process is due to the activation of a large pore in the inner mitochondrial membrane. Anti-oxidants are considered a preventive and remedial tool, and mitochondria-targeted redox-active compounds have been developed. Plant polyphenols are generally considered as anti-oxidants, and thus candidates to the role of mitochondria-protecting agents. In patch-clamp experiments, easily oxidizable polyphenols induced closure of the MPT channel. In swelling experiments with suspensions of mitochondria, high (20-50 microM) concentrations of quercetin, the most efficient inhibitor, promoted instead the onset of the MPT. Chelators of Fe(2+/3+) and Cu(+/2+) ions counteracted this effect. Fluorescent indicators of superoxide production confirmed that quercetin potentiates O(2)(*-) generation by isolated mitochondria and cultured cells. Since this was not affected by chelating Fe and Cu ions, the MPT-inducing effect can be ascribed to a "secondary", metal ion-catalyzed production of ROS. These results are a direct demonstration of the ambivalent redox character of polyphenols. Their mode of action in vivo cannot be taken for granted, but needs to be experimentally verified.
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: De Marchi
authors.forename: Lucia
authors.initials: L
authors.lastname: Biasutto
authors.forename: Spiridione
authors.initials: S
authors.lastname: Garbisa
authors.forename: Antonio
authors.initials: A
authors.lastname: Toninello
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
mesh_terms: D005419:Flavonoids / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D010084:Oxidation-Reduction; D010636:Phenols / Q000494:pharmacology*; D059808:Polyphenols; D011794:Quercetin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D005419:Flavonoids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010636:Phenols; D059808:Polyphenols; D017382:Reactive Oxygen Species; D013481:Superoxides; D011794:Quercetin