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Edelfosine and perifosine disrupt hepatic mitochondrial oxidative phosphorylation and induce the permeability transition.

Burgeiro, A; Pereira, CV; Carvalho, FS; Pereira, GC; Mollinedo, F; Oliveira, PJ; (2013) Edelfosine and perifosine disrupt hepatic mitochondrial oxidative phosphorylation and induce the permeability transition. Mitochondrion , 13 (1) pp. 25-35. 10.1016/j.mito.2012.11.003.

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Abstract

Edelfosine and perifosine are alkylphospholipids that have been intensively studied as potential antitumor agents. Apoptotic cell death caused by these two compounds is mediated, at least in part, through mitochondria. Additionally, previous works demonstrated that edelfosine induces changes in mitochondrial membrane permeability that are somehow reduced by using cyclosporin A. Therefore, the objective of the present study was not only to confirm mitochondrial permeability transition but also identify direct effects of both ether lipids on mitochondrial hepatic fractions, namely on mitochondrial oxidative phosphorylation and generation of hydrogen peroxide (H(2)O(2)) through the respiratory chain. Results show that edelfosine and perifosine inhibit mitochondrial respiration and decrease transmembrane electric potential. However, despite these effects, edelfosine and perifosine were still able to induce mitochondrial permeability transition in non-energized mitochondria. Interestingly, edelfosine decreased H(2)O(2) production through the respiratory chain. In conclusion, the present work demonstrates previously unknown alterations of mitochondrial physiology directly induced by edelfosine and perifosine. The study is relevant in the understanding of mitochondrial-target effects of both compounds, as well as to acknowledge possible toxic responses in non-tumor organs.

Type: Article
Title: Edelfosine and perifosine disrupt hepatic mitochondrial oxidative phosphorylation and induce the permeability transition.
Location: Netherlands
DOI: 10.1016/j.mito.2012.11.003
Keywords: Animals, Antineoplastic Agents, Hydrogen Peroxide, Male, Membrane Potential, Mitochondrial, Mitochondrial Membranes, Oxidative Phosphorylation, Permeability, Phospholipid Ethers, Phosphorylcholine, Rats, Wistar
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: http://discovery.ucl.ac.uk/id/eprint/1462183
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