title: Cytotoxicity of mitochondria-targeted resveratrol derivatives: interactions with respiratory chain complexes and ATP synthase.
abstract: We recently reported that mitochondria-targeted derivatives of resveratrol are cytotoxic in vitro, selectively inducing mostly necrotic death of fast-growing and tumoral cells when supplied in the low μM range (N. Sassi et al., Curr. Pharm. Des. 2014). Cytotoxicity is due to H2O2 produced upon accumulation of the compounds into mitochondria. We investigate here the mechanisms underlying ROS generation and mitochondrial depolarization caused by these agents. We find that they interact with the respiratory chain, especially complexes I and III, causing superoxide production. "Capping" free hydroxyls with acetyl or methyl groups increases their effectiveness as respiratory chain inhibitors, promoters of ROS generation and cytotoxic agents. Exposure to the compounds also induces an increase in the occurrence of short transient [Ca(2+)] "spikes" in the cells. This increase is unrelated to ROS production, and it is not the cause of cell death. These molecules furthermore inhibit the F0F1 ATPase. When added to oligomycin-treated cells, the acetylated/methylated ones cause a recovery of the cellular oxygen consumption rates depressed by oligomycin. Since a protonophoric futile cycle which might account for the uncoupling effect is impossible, we speculate that the compounds may cause the transformation of the ATP synthase and/or respiratory chain complex(es) into a conduit for uncoupled proton translocation. Only in the presence of excess oligomycin the most effective derivatives appear to induce the mitochondrial permeability transition (MPT) within the cells. This may be considered to provide circumstantial support for the idea that the ATP synthase is the molecular substrate for the MPT pore.
authors.affiliation: Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy; CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Sassi
authors.affiliation: CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy; Department of Chemical Sciences, Via F. Marzolo 1, 35131 Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattarei
authors.affiliation: Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Azzolini
authors.affiliation: Department of Biology, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Ildiko'
authors.initials: I
authors.lastname: Szabo'
authors.affiliation: Department of Chemical Sciences, Via F. Marzolo 1, 35131 Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Paradisi
authors.affiliation: Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy; CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
authors.affiliation: Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy; CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy. Electronic address: lucia.biasutto@cnr.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Biasutto
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D004579:Electron Transport; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D006180:Proton-Translocating ATPases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D013267:Stilbenes; D006861:Hydrogen Peroxide; D006180:Proton-Translocating ATPases; D000077185:Resveratrol; D002118:Calcium
keywords: ATP synthase; Mitochondria; ROS; Respiratory chain; Resveratrol; Triphenylphosphonium