title: Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore.
abstract: A unique phenomenon of mitochondria-targeted protonophores is described. It consists in a transmembrane H(+)-conducting fatty acid cycling mediated by penetrating cations such as 10-(6'-plastoquinonyl)decyltriphenylphosphonium (SkQ1) or dodecyltriphenylphosphonium (C(12)TPP). The phenomenon has been modeled by molecular dynamics and directly proved by experiments on bilayer planar phospholipid membrane, liposomes, isolated mitochondria, and yeast cells. In bilayer planar phospholipid membrane, the concerted action of penetrating cations and fatty acids is found to result in conversion of a pH gradient (DeltapH) to a membrane potential (Deltapsi) of the Nernstian value (about 60 mV Deltapsi at DeltapH = 1). A hydrophobic cation with localized charge (cetyltrimethylammonium) failed to substitute for hydrophobic cations with delocalized charge. In isolated mitochondria, SkQ1 and C(12)TPP, but not cetyltrimethylammonium, potentiated fatty acid-induced (i) uncoupling of respiration and phosphorylation, and (ii) inhibition of H(2)O(2) formation. In intact yeast cells, C(12)TPP stimulated respiration regardless of the extracellular pH value, whereas a nontargeted protonophorous uncoupler (trifluoromethoxycarbonylcyanide phenylhydrazone) stimulated respiration at pH 5 but not at pH 3. Hydrophobic penetrating cations might be promising to treat obesity, senescence, and some kinds of cancer that require mitochondrial hyperpolarization.
authors.affiliation: Belozersky Institute of Physico-Chemical Biology and Institute of Mitoengineering, Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Fedor F
authors.initials: FF
authors.lastname: Severin
authors.forename: Inna I
authors.initials: II
authors.lastname: Severina
authors.forename: Yury N
authors.initials: YN
authors.lastname: Antonenko
authors.forename: Tatiana I
authors.initials: TI
authors.lastname: Rokitskaya
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Cherepanov
authors.forename: Elena N
authors.initials: EN
authors.lastname: Mokhova
authors.forename: Mikhail Yu
authors.initials: MY
authors.lastname: Vyssokikh
authors.forename: Antonina V
authors.initials: AV
authors.lastname: Pustovidko
authors.forename: Olga V
authors.initials: OV
authors.lastname: Markova
authors.forename: Lev S
authors.initials: LS
authors.lastname: Yaguzhinsky
authors.forename: Galina A
authors.initials: GA
authors.lastname: Korshunova
authors.forename: Nataliya V
authors.initials: NV
authors.lastname: Sumbatyan
authors.forename: Maxim V
authors.initials: MV
authors.lastname: Skulachev
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Skulachev
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000378:metabolism; D000818:Animals; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000378:metabolism; D002412:Cations / Q000378:metabolism*; D016922:Cellular Senescence; D003600:Cytosol / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007037:Hypothyroidism / Q000503:physiopathology; D007700:Kinetics; D008928:Mitochondria / Q000502:physiology*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology; D051336:Mitochondrial Membranes / Q000502:physiology*; D009369:Neoplasms / Q000473:pathology; D009765:Obesity / Q000503:physiopathology; D009861:Onium Compounds / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000378:metabolism; D010971:Plastoquinone / Q000031:analogs & derivatives / Q000494:pharmacology; D011522:Protons; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C532038:10-(6'-plastoquinonyl)decyltriphenylphosphonium; D002412:Cations; D005227:Fatty Acids; D009861:Onium Compounds; D009943:Organophosphorus Compounds; D011522:Protons; D017382:Reactive Oxygen Species; D015060:1,2-Dipalmitoylphosphatidylcholine; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D010971:Plastoquinone; C013289:tetraphenylphosphonium