Edelfosine and perifosine disrupt hepatic mitochondrial oxidative phosphorylation and induce the permeability transition |
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Authors: | Ana Burgeiro Cláudia V Pereira Filipa S Carvalho Gonçalo C Pereira Faustino Mollinedo Paulo J Oliveira |
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Institution: | 1. CNC — Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal;2. BEB — PhD Programme in Experimental Biology and Biomedicine, CNC — Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal;3. Department of Life Sciences, University of Coimbra, Coimbra, Portugal;4. Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain |
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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 (H2O2) 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 H2O2 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. |
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