Brown‐adipose‐tissue mitochondria: the regulation of the 32 000‐<i>M</i><sub>r</sub> uncoupling protein by fatty acids and purine nucleotides

Rial, Eduardo; Poustie, Alison; Nicholls, David G.

doi:10.1111/j.1432-1033.1983.tb07815.x

Cited by 181 publications

(104 citation statements)

References 24 publications

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“…According to Rial et al [30] and Klingenberg [16], not only wide-spread natural fatty acids like palmitate, stearate and oleate, but also carboxylic acids with a shorter hydrocarbon chain are still competent (but at higher concentrations) in activating the thermogenin-mediated H + conductance. Recently Garlid showed [27] that hexane suifonate can substitute for palmitate in activating the H ~ conductance via thermogenin, the half-maximal concentration of hexane sulfonate being more than 10 ~ times higher than that of palmitate.…”

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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Section: Fatty Acid Circuit Hypothesismentioning

confidence: 99%

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

1991

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“…Apart from other types of mitochondria they possess the uncoupling protein (UP), a unique proton translocator [2,3], converting A/~H + into heat. H + fluxes through the UP are inhibited by purine nucleotides [4][5][6][7][8] and activated by fatty acids [3,[8][9][10]. Both regulatory mechanisms were also demonstrated in a reconstituted system [3], but the activation by fatty acids was disputed in another laboratory [2].…”

Section: Introductionmentioning

confidence: 99%

“…The stronger uncoupling effect of FA in BAT mitochondria clearly reflects activation of H ÷ transport through UP and correlates with the exclusive occurrence of UP in BAT [9,10]. In our work we used a controlled removal of endogenous fatty acid from BAT mitochondria by a carnitine cycle [8,9,[18][19][20] in order to estimate the interrelationship between effects of purine nucleotides and fatty acids on UP function.…”

Section: Introductionmentioning

confidence: 99%

Carnitine cycle in brown adipose tissue mitochondria as a tool for studying the regulatory role of fatty acids in the uncoupling protein function

et al. 1989

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A concerted function of purine nucleotide (PN) binding and fatty acid (FA) release from the uncoupling protein (UP) resulting in the maximum coupling (potential) of brown adipose tissue (BAT) mitochondria was demonstrated. The uncoupling effect of FA was studied (at 4 mM MgCI2): 17 nmol oleate per mg protein caused a slight uncoupling with 8.9 mM ATP but with ATP below 3.6 mM almost total uncoupling was achieved. This shows that the PN-controUed gate can be stabilized in the closed conformation (with 8.9 mM ATP), also when FA is bound to UP. The sensitivity of the FA effect to ATP proves that oleate directly interacts with UP. The closed conformation of the H ÷ channel of UP is then abolished by oleate when a lower free ATP concentration is maintained outside.Fatty acid uncoupling; Uncoupling protein; Brown adipose tissue mitochondria; H + channel

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“…It was suggested that UP exists in the membrane as a functional dimer [15, 251 containing a single nucleotide-binding site on the cytosolic surface [19,26,271 of the inner mitochondrial membrane and that both H ' and C1-are transported via a single channel in UP [20,281. However, a lack of any competition between H + and C1-transport, occurring simultaneously in KCl, indicated that two distinct and independent pathways for H ' and C1-translocation via UP might exist [29].…”

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confidence: 99%

Control of uncoupling protein in brown‐fat mitochondria by purine nucleotides

Kopecký

Ježek

Drahota

et al. 1987

European Journal of Biochemistry

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The uncoupling protein (UP) of isolated brown adipose tissue mitochondria was studied with respect to the mechanism of control of UP function by purine nucleotides. Passive transport of H + and C1-was followed simultaneously in a KC1 medium. With both GDP and ATP a higher sensitivity of C1-transport (apparent Ki = 2.2 pM and 4.7 pM respectively) than of H + transport (apparent Kj = 7.7 pM and 34 pM respectively) was observed. Chemical modification of isolated mitochondria by diazobenzenesulfonate (DABS) up to 75 pmol/mg protein did not affect the transport, its ionic selectivity and regulation by endogenous free fatty acids. In contrast, the sensitivity to purine nucleotides of both H + and CI-translocation was decreased (apparent Ki increased 71 and 47 times respectively). DABS decreased the affinity of [3H]GDP for the specific nucleotide-binding site on mitochondria (Kd increased from 2.7 pM to 13 pM) and depressed, to a smaller extent, the GDP-binding capacity.Correlation between occupancy of the specific nucleotide-binding site by GDP and inhibition of transport yielded a linear relationship for C1-transport in control mitochondria. For H t transport in the control, and for both H ' and C1-transports in DABS-treated mitochondria, a biphasic correlation was obtained.The results show that different structural parts of UP are involved in transport and its control by the regulatory ligands and that, in addition to binding of purine nucleotides to UP, the inhibition of ion transport by purine nucleotides depends on an intrinsic factor modulating the inhibitory effect.The thermogenic function of brown adipose tissue mitochondria results from the dissipation of the respirationgenerated electrochemical potential gradient of protons via a regulatable H' channel (for reviews see [I, 2]), the so-called uncoupling protein (UP [3]), or thermogenin [l]. This protein is distinct from mitochondrial H + -ATPase [4 -61 and is specific for brown-fat mitochondria [7, 81. The UP is most probably also involved in the unusually high permeability of brown-fat mitochondria to anions (especially C1-and Br -, but also NO;) at neutral pH [9 -111. However, the physiological meaning of the latter transport function of UP is not clear.Both H' and anion permeability of brown-fat mitochondria are decreased by purine nucleotide diphosphates and triphosphates (GDP, ADP,GTP and ATP [9 -12]), while removal of endogenous free fatty acids specifically diminishes only the H + permeability [9,10,13, 141 ular mass to be close to 32 kDa [24] and showed a high degree of homology between rat and hamster UP [23]. A significant structural similarity was also found between UP and the mitochondrial ATP/ADP carrier and it was suggested [21] that these two proteins, together with some other mitochondrial anion carriers, are derived from the same ancestral gene. The mechanism of ion translocation through UP and the control by purine nucleotides and free fatty acids are still poorly understood. It was suggested that UP exists in the membrane as a functional di...

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Brown‐adipose‐tissue mitochondria: the regulation of the 32 000‐M_r uncoupling protein by fatty acids and purine nucleotides

Cited by 181 publications

References 24 publications

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

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

Carnitine cycle in brown adipose tissue mitochondria as a tool for studying the regulatory role of fatty acids in the uncoupling protein function

Control of uncoupling protein in brown‐fat mitochondria by purine nucleotides

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Brown‐adipose‐tissue mitochondria: the regulation of the 32 000‐Mr uncoupling protein by fatty acids and purine nucleotides

Cited by 181 publications

References 24 publications

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

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

Carnitine cycle in brown adipose tissue mitochondria as a tool for studying the regulatory role of fatty acids in the uncoupling protein function

Control of uncoupling protein in brown‐fat mitochondria by purine nucleotides

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Brown‐adipose‐tissue mitochondria: the regulation of the 32 000‐M_r uncoupling protein by fatty acids and purine nucleotides