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A unique phenomenon of mitochondria-targeted protonophores is described. It consistsin a transmembrane [H.sup.+]-conducting fatty acid cycling mediated by penetrating cations such as 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1) or dodecyltriphenylphosphonium ([C.sub.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 ([DELTA]pH) to a membrane potential ([DELTA]/[psi]) of the Nernstian value (about 60 mV [DELTA][psi]/at [DELTA]pH = 1). A hydrophobic cation with localized charge (cetyltrimethylammonium) failed to substitute for hydrophobic cations with delocalized charge. In isolated mitochondria, SkQ1 and [C.sub.12]TPP, but not cetyltrimethylammonium, potentiated fattyacid-induced (i) uncoupling of respiration and phosphorylation, and (ii) inhibition of [H.sub.2][O.sub.2] formation. In intactyeast cells, [C.sub.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. mild uncoupling | membrane | Mitochondria-targeted uncoupler | penetrating ion | antioxidant www.pnas.org/cgi/doi/10.1073/pnas.0910216107