title: Membrane depolarization of isolated rat liver mitochondria attenuates permeability transition pore opening and oxidant production.
abstract: It has been suggested that one key feature of mitochondrial permeability transition (PT) regulation is its control by the proton electrochemical gradient and that depolarization favors pore opening, swelling, and reactive oxygen species (ROS) production. Moreover, ROS have been suggested to facilitate the process of mitochondrial PT pore opening. The aim of this study was to show that collapsing the mitochondrial membrane potential with the mitochondrial uncoupler, carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), at concentrations of up to 10 microM, does not induce mitochondrial swelling and, in fact, stabilizes mitochondria exposed to oxidant, protecting them from tert-butyl hydroperoxide (TBH)-induced high-amplitude swelling. FCCP decreased polyethylene glycol-induced mitochondrial contraction following exposure to TBH, indicating closing of the PT mega-channel. In the presence of the calcium uniporter inhibitor ruthenium red, FCCP induced PT due to suppression of calcium efflux. Under PT-favorable conditions, ROS production was evaluated in mitochondria following treatments with TBH, inorganic phosphate, or FCCP (with or without ruthenium red). FCCP alone and in combination with ruthenium red attenuated mitochondria-derived ROS production. FCCP also decreased the augmented ROS production induced by inorganic phosphate. It is concluded that mitochondrial depolarization protects and prevents high-amplitude swelling and PT-derived ROS production.
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Aronis
authors.forename: Rita
authors.initials: R
authors.lastname: Komarnitsky
authors.forename: Shani
authors.initials: S
authors.lastname: Shilo
authors.forename: Oren
authors.initials: O
authors.lastname: Tirosh
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D019069:Cell Respiration / Q000502:physiology; D004396:Coloring Agents / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology*; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010710:Phosphates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012430:Ruthenium Red / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014475:Uncoupling Agents / Q000494:pharmacology; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D004396:Coloring Agents; D016877:Oxidants; D010710:Phosphates; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012430:Ruthenium Red; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D020122:tert-Butylhydroperoxide; D002118:Calcium