Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12857/115518
Title: Cytotoxicity of mitochondria-targeted resveratrol derivatives: interactions with respiratory chain complexes and ATP synthase
Authors: Sassi, Nicola 
Mattarei, Andrea 
Azzolini, Michele
Szabo', Ildiko'
Paradisi, Cristina 
Zoratti, Mario 
Biasutto, Lucia 
Keywords: ATP synthase;Mitochondria;ROS;Respiratory chain;Resveratrol;Triphenylphosphonium
Keywords Plus: PERMEABILITY TRANSITION PORE;CELL-DEATH;CONDUCTANCE STATE;REDOX REGULATION;INNER MEMBRANE;INHIBITION;CHANNEL;CANCER;POLYPHENOLS;F-1-ATPASE
Mesh headings: Electron Transport;Mitochondria;Proton-Translocating ATPases;Stilbenes
Secondary Mesh headings: Animals;Calcium;Calcium Signaling;Cell Line, Tumor;Hydrogen Peroxide;Mice;Microscopy, Fluorescence;Oxygen Consumption;Reactive Oxygen Species;Resveratrol
Issue Date: Oct-2014
Publisher: ELSEVIER SCIENCE BV
Journal: Biochimica et biophysica acta 
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.
URI: http://hdl.handle.net/20.500.12857/115518
ISSN: 0006-3002
DOI: 10.1016/j.bbabio.2014.06.010
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