2,4-Dinitrophenol and Carbonylcyanide p-Trifluoromethoxyphenylhydrazone Activate the Glutathione S-Conjugate Transport ATPase of Human Erythrocyte Membranes

Winter, Charles G.; DeLuca, Donald C.; Szumilo, Halina

doi:10.1006/abbi.1994.1406

Cited by 19 publications

(7 citation statements)

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“…Remarkably, UCP3 differed from the chemical uncoupler in that the proton leak was accompanied by a decrease not in the ATP content of cells but in ADP. In consequence the ATP/ADP ratio was increased in UCP3-overexpressing cells in contrast to the decrease induced after treatment with CCCP (29). This finding suggests a dissociation between the effect of UCP3 on mitochondrial membrane potential and ATP synthesis and therefore questions the consideration of UCP3 as an uncoupler of oxidative phosphorylation.…”

Section: Discussionmentioning

confidence: 87%

Overexpression of UCP3 in cultured human muscle lowers mitochondrial membrane potential, raises ATP/ADP ratio, and favors fatty acid versus glucose oxidation

Garcı́a-Martı́nez¹,

Sibille

Solanes³

et al. 2001

FASEB j.

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The skeletal muscle mitochondrial uncoupling protein-3 (UCP3) promotes substrate oxidation, but direct evidence for its metabolic role is lacking. Here, we show that UCP3 overexpression in cultured human muscle cells decreased mitochondrial membrane potential (DYm). Despite this, the ATP content was not significantly decreased compared with control cells, whereas ADP content was reduced and thus the ATP/ADP ratio raised. This finding was contrasts with the effect caused by the chemical protonophoric uncoupler, CCCP, which lowered DYm, ATP, and the ATP/ADP ratio. UCP3-overexpression enhanced oxidation of oleate, regardless of the presence of glucose, whereas etomoxir, which blocks fatty acid entry to mitochondria, suppressed the UCP3 effect. Glucose oxidation was stimulated in UCP3-overexpressing cells, but this effect was inhibited by oleate. UCP3 caused weak increase of both 2-Deoxyglucose uptake and glycolytic rate, which differed from the marked stimulation by CCCP. We concluded that UCP3 promoted nutrient oxidation by lowering DYm and enhanced fatty acid-dependent inhibition of glucose oxidation. Unlike the uncoupler CCCP, however, UCP3 raised the ATP/ADP ratio and modestly increased glucose uptake and glycolysis. We propose that this differential effect provides a biological significance to UCP3, which is up-regulated in metabolic stress situations where it could be involved in nutrient partitioning.

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Section: Discussionmentioning

confidence: 87%

Overexpression of UCP3 in cultured human muscle lowers mitochondrial membrane potential, raises ATP/ADP ratio, and favors fatty acid versus glucose oxidation

Garcı́a-Martı́nez¹,

Sibille

Solanes³

et al. 2001

FASEB j.

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“…However, uncouplers are known to have additional intracellular targets, e.g., plasma membrane potential and ΔpH [9], [10]. It has also been shown that DNP inhibits chloride channel of erythrocytes [11] and blocks glutathione-S-conjugate forming ATP-ase [12]. Comparison of toxic doses for mice with uncoupling concentrations for isolated mitochondria has revealed poor correlation of these parameters for a large set of DNP analogues as well as for some other uncouplers [13].…”

Section: Introductionmentioning

confidence: 99%

Penetrating Cations Enhance Uncoupling Activity of Anionic Protonophores in Mitochondria

et al. 2013

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Protonophorous uncouplers causing a partial decrease in mitochondrial membrane potential are promising candidates for therapeutic applications. Here we showed that hydrophobic penetrating cations specifically targeted to mitochondria in a membrane potential-driven fashion increased proton-translocating activity of the anionic uncouplers 2,4-dinitrophenol (DNP) and carbonylcyanide-p-trifluorophenylhydrazone (FCCP). In planar bilayer lipid membranes (BLM) separating two compartments with different pH values, DNP-mediated diffusion potential of H+ ions was enhanced in the presence of dodecyltriphenylphosphonium cation (C12TPP). The mitochondria-targeted penetrating cations strongly increased DNP- and carbonylcyanide m-chlorophenylhydrazone (CCCP)-mediated steady-state current through BLM when a transmembrane electrical potential difference was applied. Carboxyfluorescein efflux from liposomes initiated by the plastoquinone-containing penetrating cation SkQ1 was inhibited by both DNP and FCCP. Formation of complexes between the cation and CCCP was observed spectophotometrically. In contrast to the less hydrophobic tetraphenylphosphonium cation (TPP), SkQ1 and C12TPP promoted the uncoupling action of DNP and FCCP on isolated mitochondria. C12TPP and FCCP exhibited a synergistic effect decreasing the membrane potential of mitochondria in yeast cells. The stimulating action of penetrating cations on the protonophore-mediated uncoupling is assumed to be useful for medical applications of low (non-toxic) concentrations of protonophores.

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“…A reduction of membrane fluidity might inhibit the uptake of DNP by the nerve terminals, leading to the reduced activity of this agent. The lipophilicity and monoanionic character of DNP are very important for the effective action of DNP (Winter et al, 1994). A reduction in temperature from 360C to 240C increases the evoked release of transmitter, as shown recently (Nishimura et al, 1993a).…”

Section: Discussionmentioning

confidence: 94%

Dependence on temperature of the effect of dinitrophenol on the release of transmitter quanta at neuromuscular junctions in the mouse diaphragm

Nishimura

Taquahashi

Fujita

et al. 1996

British J Pharmacology

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1 The frequencies (F, s-1) of miniature endplate potentials and the quantal content (m) of endplate potentials were measured intracellularly and simultaneously at mouse diaphragm endplates in a bathing solution that contained 0.6 mM Ca2" ions and 5 mM Mg2" ions.2 Twin pulses at 4 ms intervals gave the quantal contents of the first (ml) and second (m2) responses. The ratio of m2/ml was taken as an indicator of the temporal facilitation of the release of transmitter. 3 Dinitrophenol (DNP, 10 !M) increased the values of F and m at 36'C. This effect did not depend on extracellular Ca" ions.4 The potentiating effect of DNP disappeared at 24°C but the value of m2/ml remained constant. 5 These results suggest that the effect of DNP is modifiable by temperature which can affect systems that control the intracellular metabolism of Ca2" ions.

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2,4-Dinitrophenol and Carbonylcyanide p-Trifluoromethoxyphenylhydrazone Activate the Glutathione S-Conjugate Transport ATPase of Human Erythrocyte Membranes

Cited by 19 publications

References 0 publications

Overexpression of UCP3 in cultured human muscle lowers mitochondrial membrane potential, raises ATP/ADP ratio, and favors fatty acid versus glucose oxidation

Overexpression of UCP3 in cultured human muscle lowers mitochondrial membrane potential, raises ATP/ADP ratio, and favors fatty acid versus glucose oxidation

Penetrating Cations Enhance Uncoupling Activity of Anionic Protonophores in Mitochondria

Dependence on temperature of the effect of dinitrophenol on the release of transmitter quanta at neuromuscular junctions in the mouse diaphragm

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