Penetrating Cation/fatty Acid Anion Pair As a Mitochondria-targeted Protonophore

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Jan 19

PMID 20080732

Citations 58

Authors

Fedor F Severin

Inna I Severina

Yury N Antonenko

Tatiana I Rokitskaya

Dmitry A Cherepanov

Elena N Mokhova

Mikhail Yu Vyssokikh

Antonina V Pustovidko

Olga V Markova

Lev S Yaguzhinsky

Galina A Korshunova

Nataliya V Sumbatyan

Maxim V Skulachev

Vladimir P Skulachev

Affiliations

Soon will be listed here.

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.

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