title: Edelfosine and perifosine disrupt hepatic mitochondrial oxidative phosphorylation and induce the permeability transition.
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.
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Burgeiro
authors.forename: Cláudia V
authors.initials: CV
authors.lastname: Pereira
authors.forename: Filipa S
authors.initials: FS
authors.lastname: Carvalho
authors.forename: Gonçalo C
authors.initials: GC
authors.lastname: Pereira
authors.forename: Faustino
authors.initials: F
authors.lastname: Mollinedo
authors.forename: Paulo J
authors.initials: PJ
authors.lastname: Oliveira
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects*; D010742:Phospholipid Ethers / Q000378:metabolism*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000378:metabolism; D017208:Rats, Wistar
chemical_list: D000970:Antineoplastic Agents; D010742:Phospholipid Ethers; D010767:Phosphorylcholine; C026659:edelfosine; C105905:perifosine; D006861:Hydrogen Peroxide