The ATP/ADP‐antiporter is involved in the uncoupling effect of fatty acids on mitochondria

Andreyev, Alexander Y.; Bondareva, T. O.; Dedukhova, V.I.; Mokhova, E. N.; Skulachev, Vladimir P.; Tsofina, L. M.; Volkov, N. I.; Vygodina, Tatiana V.

doi:10.1111/j.1432-1033.1989.tb14867.x

Cited by 283 publications

(179 citation statements)

References 30 publications

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“…Without C 12 TPP, Catr prevented palmitate-induced decrease in H 2 O 2 formation by mitochondria (Fig. 3E), thus confirming an original observation made by our group (30). Similar action of Catr was revealed when fatty acid uncoupling was potentiated by TPP (24).…”

Section: Discussionsupporting

confidence: 88%

Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore

Severin

Severina

Antonenko

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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182

115

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A unique phenomenon of mitochondria-targeted protonophores is described.ItconsistsinatransmembraneH þ -conductingfattyacidcycling 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 (ΔpH) to a membrane potential (Δψ) of the Nernstian value (about 60 mV Δψ at ΔpH ¼ 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, potentiatedfattyacid-induced(i)uncouplingofrespirationandphosphorylation, 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 (trifluoromethoxycarbonylcyanidephenylhydrazone)stimulatedrespiration 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 S ome decrease in mitochondrial membrane potential (Δψ) in the resting state may be favorable in treating obesity and hypothyroidism as well as in preventing senescence and certain types of cancer [for reviews, see refs. 1, 2]. In the first two cases, Δψ lowering stimulates respiratory metabolism. As to senescence and cancer, such an effect seems to be related to a decrease in production of reactive oxygen species (ROS) in mitochondria. ROS, in turn, were assumed to mediate senescence and some steps of cancerogenesis (2, 3). As was shown in our group (4), there is a very steep dependence of mitochondrial ROS formation on Δψ. Small (10-15%) lowering of Δψ resulted in ten-fold decrease in the ROS production rate (4). In isolated mitochondria, this can be achieved by adding a low concentration of a protonophorous uncoupler (4-6). This approach, called "mild uncoupling" (4, 6), was recently used by Padalko (7) and by Kowaltowski and coworkers (8) to prolong the lifespan of Drosophila and mice, respectively. However, long-term treatment of animals with uncouplers results in toxic side effects (9).In this paper, we put forward an alternative approach based on the use of synthetic cations that easily penetrate through biological membranes. Penetrating ions were suggested by our group to reveal electric potential difference across mitochondrial membrane (9, 10). In tetraphenylphosphonium (TPP), a typical representative of such ions, the positive charge is strongly displaced over four phenyl residues. As a result, water dipoles cannot be held by t...

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Section: Discussionsupporting

confidence: 88%

Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore

Severin

Severina

Antonenko

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

182

115

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“…Further, CAtr incubation promoted (i) the appearance of the biphasic behavior in Jtt+--dW and (ii) an increase in the membrane potential (Fig. 2D) of the fetal mitochondria, in agreement with recent findings [15][16][17].…”

Section: Malonatesupporting

confidence: 91%

“…2C), similar to that triggered by ATP ( Fig. 2A), further reinforces the functional homology between UCP and the ATP/ADP antiporter as thermoregulatory elements of uncoupled respiration [15][16][17]22]. At least, under a situation where the adenine nucleotide content of mitochondria is below 30% of its normal level; that is, m the fetal liver [I, 4,5] or under in vitro conditions of adenine nucleotide depletion ( Fig.…”

Section: Discussionsupporting

confidence: 71%

“…The UCP and the ATP/ADP antiporter show structural and, to some extent, functional homc,logy [28] (for reviews see [22,29]). GDP is a regulatory molecule of UCP activity, and in contrast to CAtr, has been shown to not inhibit the palmitate-induced stimulation of respiration in mitochondria from skeletal muscle and liver [15]. The surprising finding that GDP pre-incubation of fetal mitochondria promotes a decrease in LN+ and introduces the characteristic biphasic proton conductance behavior (Fig.…”

Section: Discussionmentioning

confidence: 95%

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Interaction of adenine nucleotides with the adenine nucleotide translocase regulates the developmental changes in proton conductance of the inner mitochondrial membrane

Valcarce

Vuezva

1991

FEBS Letters

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2-h-old neonatal liver mitochondria, when depleted or" adenine nucleotides, showed an "ohmic" current--voltage relationship and a higher passive proton i~rmeability of the membrane, resembling fetal mitochondrial behaviors for the proton conductanc©. Incubation of fetal mitochondria with ATP, GDP or carboxyatractylosicle promoted a significant reductio~t in the passive proton permeability of the membrane and the appearance of the characteristic biphasic behavior for the proton conductance. It is concluded that the postnatal increase in intramitochondrial adenine nucleotide corto~'ntration promotes, by the interaction of the nucleotides with the adenine nucleotide translocase, the reduction in the passive proton permeability of the mitochondrial membrane, allowing efficient energy conservation in the neonatal liver.

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“…These proteins, localized in the inner mitochondrial membrane, are thermogenin in brown fat (uncoupling by fatty acids [I]), the ATP/ADP anti porter in other tissues (uncoupling by fatty acids and dinitrophenol [2]), and a still unknown protein(s) acting as steroid hormone receptor(s) in liver and heart mitochondria (FCCP and related uncouplers) [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Effect of cyclosporin A on energy coupling in pea stem mitochondria

et al. 1995

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Effect of cycIosporin A on energy coupling in pea stem mitochondria is studied. It is found that incubation of mitochondria with 100 nM FCCP and/or CAtr, oligomycin, CaCI 2 , palmitate and ADP results, after some lag phase, in a collapse of .:11/1 generated by succinate oxidation in the presence of rotenone. CycIosporin A (0.2-0.8 nmoUmg mitochondrial protein) markedly increases the lag phase. The cycIosporin A effect requires dithioerythritol to be added to the isolation medium. Metabisulphite fails to substitute for dithioerythritol. The relationships between these effects and cycIosporin A-sensitive mitochondrial permeability transition in animal mitochondria are discussed.

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The ATP/ADP‐antiporter is involved in the uncoupling effect of fatty acids on mitochondria

Cited by 283 publications

References 30 publications

Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore

Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore

Interaction of adenine nucleotides with the adenine nucleotide translocase regulates the developmental changes in proton conductance of the inner mitochondrial membrane

Effect of cyclosporin A on energy coupling in pea stem mitochondria

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