Carboxyatractylate inhibits the uncoupling effect of free fatty acids

Andreyev, Alexander Y.; Bondareva, T. O.; Dedukhova, V.I.; Mokhova, E. N.; Skulachev, Vladimir P.; Volkov, N. I.

doi:10.1016/0014-5793(88)81436-4

Cited by 143 publications

(89 citation statements)

References 6 publications

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“…It has to be stressed that AAC is most likely not the sole protein facilitating the protonophoric action of fatty acids, as carboxyatractyloside does not prevent fatty-acid-induced uncoupling completely (see [9,10,141 and the present work). Moreover, recent observations of Bodrova et al [34] and ourselves (Wojtczak, L. and Wicckowski, M. R., unpublished results) provide evidence that other mitochondrial anion carriers my also contribute to the protonophoric function of fatty acid cycling.…”

Section: Discussionmentioning

confidence: 69%

Photomodification of Mitochondrial Proteins by Azido Fatty Acids and Its Effect on Mitochondrial Energetics

Schönfeld

Ježek

Belyaeva

et al. 1996

European Journal of Biochemistry

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Azido derivatives of long-chain fatty acids, 12-(4-azido-2-nitrophenylamino)dodecanoic acid (N3-NpNH-Lau) and 16-(4-azido-2-nitrophenyla~ino)hexadecanoic acid (N,-NpNH-Pam), were used to study the mechanism of the protonophoric function of long-chain fatty acids in mitochondrial membranes. N,-NpNH-Lau was found to increase resting-state respiration and decrease the membrane potential in a dosedependent way in a manner similar to that of the natural fatty acid, myristate. Both effects of N,-NpNHLau as well as of the myristate were reversed or prevented by the inhibitor of the mitochondrial ADP/ATP carrier (AAC), carboxyatractyloside. This protective effect of carboxyatractyloside was well expressed in rat heart mitochondria and less so in mitochondria within digitonin-permeabilized Ehrlich ascites tumour cells. Photomodification of Ehrlich ascites tumour mitochondria by ultraviolet irradiation in the presence of N,-NpNH-Lau made them more resistant to the uncoupling effect of myristate, and photomodification of rat heart mitochondria resulted in a strong inhibition of AAC which could not be reversed by serum albumin.Photolabelling of rat heart mitochondria with tritiated N,-NpNH-Pam revealed around 10 labelled bands on SDS/polyacrylamide gel electrophoresis. Based on immunodetection with a specific antibody, one of them, corresponding to 30 kDa, was identified as AAC. Specific interaction of AAC with azido fatty acids was confirmed by a high radiolabelling of this band.The role of fatty acids in fine control of the efficiency of oxidative phosphorylation is discussed.Keywords: fatty acid ; ADP/ATP carrier; protonophoric activity ; uncoupling ; mitochondria.Long-chain fatty acids (in their activated form) are readily oxidized by mitochondria of most mammalian tissues, feeding electrons to the respiratory chain and thus contributing to energy production in the form of ATP. However, fatty acids also interact with mitochondrial membranes and interfere with the energycoupling system as weak uncouplers. Thus, they may play a dual role in cell energetics, being metabolites as well as regulators of oxidative phosphorylation efficiency. The uncoupling effect of fatty acids has been well known for four decades (for review, see [I]). However, the mechanism by which fatty acids decrease the efficiency of energy transformation in mitochondria is not fully understood. A direct protonophoric mechanism has been proposed [2-51, but objections have been raised based on a very slow flip-flop rate of the fatty acid anion [2,

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Section: Discussionmentioning

confidence: 69%

Photomodification of Mitochondrial Proteins by Azido Fatty Acids and Its Effect on Mitochondrial Energetics

Schönfeld

Ježek

Belyaeva

et al. 1996

European Journal of Biochemistry

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“…In particular Andreyev et al (1988) have postulated that the mitochondrial adenine nucleotide translocator would, in the presence of low concentrations of fatty acids, become a heat generator in muscle as well as in liver, without losing its sensitivity to the classical inhibitors. It is evident from the results of Table I that the IMM channel does not respond to these molecules and consequently that it is probably not the modified adenine nucleotide translocator involved in nonshivering thermogenesis.…”

Section: Discussionmentioning

confidence: 99%

Further investigation on the high-conductance ion channel of the inner membrane of mitochondria

Sorgato

Morán

Pinto

et al. 1989

J Bioenerg Biomembr

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By use of the patch-clamp technique, the inner membrane of mouse liver and heart mitochondria is shown to contain a highly conductive (around t00 pS in symmetrical 150 mM KC1) and voltage-dependent ion channel. This channel closely resembles that previously found in cuprizone-treated mouse liver inner mitochondrial membrane. The paper discusses the electrical properties of the channel and its possible physiological function. The reconstitution in giant liposomes of a partially purified ox heart inner membrane fraction containing the channel and the use of various inhibitors are also presented.

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“…The Ki values for CAtr inhibition (1) of oxidative phosphorylation and (2) of the fatty acid-stin:ulated respiration in the presence of the H+-ATP-synthase inhibitor, oligomycin, proved to be similar [18,[20][21][22][23].…”

Section: Fatty Acid Circuit Hypothesismentioning

confidence: 99%

Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation

1991

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Free fatty acids, natural uncouplers of oxidative phosphorylation, are shown to differ from -xrtificial ones in that they fail to increase conductance of phospholipid bilayers which are permeable for the protonated form of fatty acids but impermeable for their anionic form. Recent studies have revea|eO that uncoupling oy fatty acids in mitochondria is mediated by the ATIP/ADP an!iporter and, in brown fat, by thermogenin which is structurally very similar to the antiporter, it is suggested that both the ATP/ADP antiporter and thermogenin facilitate translocation of the fatty anions through the mitochondrial membrane.Fatty acid: Uncoupling; ATP/ADP antiporter; ThermogeninIn 1960 we proposed that uncoupling of oxidative phosphorylation is a mechanism of the urgent heat production by warm-blooded animals when the ambient temperature strongly decreases [1] (see also [2]). This propose-! was based upon our observation that i 5 rain cold exposure of pigeons previously adapted to cold stresses l~sults in a 6-fold decrease in the P/O ratio in the breast muscle mitochondria [1,2]. Such an etTect was then reproduced in the muscle mitochondria of mouse [3] and of fur seal [4].The uncoupling was shown to be abolished by adding serum albumin [2,4]. This fact could be explained suggesting that fatty acids are involved in the above effect [5] since (i) free fatty acids uncouple oxidation and phosphorylation in mitochondria as first described by Pressman and Lardy [6], and (ii) serum albumin binds fatty acids and recouples mitochondria [5]. The above suggestion was confirmed by our experiments showing that the short-term cold exposure increases the level of fatty acids both in muscle in situ and in mitochondria isolated from muscle of the cold-exposed animal. Fatty acids extracted from mitochondria of the c,)ld-exposed animals and then added to mitochondria from the nonexposed ones were found to cause uncoupling [7].The idea of thermoregulatory uncoupling mediated by fatty acids was later confirmed and extended in numerous studies on brown fat, the mammalian tissue specialized in additional heat production under cold conditions (for reviews, see [8][9][10][11][12]). In the brown fat mitochondria, the uncoupling protein (the other name, therrnogenin) has been discovered [I 3,14]. This protein increases g ÷ conductance of the brown fat mitochondrial membrane.The uncoupling activity of thermogenin was shown to require free fatty acids [11,12,[15][16][17]. It is not clear yet how fatty acids activate thcrmogen.;n as well as how they uncouple, in tissues other than brown fat where there is no thermogenin. It seems obvious that fatty acids cannot operate as well-known artificial protonophorous uncouplers such as trifluoromethoxycarbonylcyanide phenylhydrazone (Ft~.CP). In contrast to FCCP, which strongly increases the conductance of planar phospholipid bilayers and liposomes, fatty acids are almost without effect on the conductance of plapar me:nbrdne and cytochrome oxidase proteoliposom©s [181.Such an inefficiency of fatty acids as ...

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Carboxyatractylate inhibits the uncoupling effect of free fatty acids

Abstract: The ATP/ADP-antiporter inhibitors and ADP decrease the palmitate-induced stimulation of the mitochondrial respiration in the controlled state.

Cited by 143 publications

References 6 publications

Photomodification of Mitochondrial Proteins by Azido Fatty Acids and Its Effect on Mitochondrial Energetics

Photomodification of Mitochondrial Proteins by Azido Fatty Acids and Its Effect on Mitochondrial Energetics

Further investigation on the high-conductance ion channel of the inner membrane of mitochondria

Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation

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