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

Abstract

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 ...

Photoaffinity labelling of the mitochondrial uncoupling protein by [3H]azido fatty acid affects the anion channel

“…Our results are also compatible with the fatty acid cycling mechanism proposed for UcP [3,9]. According to this "FAprotonophore model" [3] anionic FA are rather transport substrates of UcP.…”

“…Their action was later described as decoupling [15] and a novel point of view came with the fatty acid cycling hypothesis [3,9]. Any specific interaction with an integral mitochondrial membrane protein(s) requires the existence of a specific receptoric site in such a protein.…”

“…UcP function [3 8] is the uniport of monovalent unipolar anions [7] including the uniport of the anionic forms of fatty acids [3][4][5][6]. The latter leads to the fatty acid cycling uncoupling mechanism originally suggested by Skulachev for the ADP/ADP antiporter and UcP [9] (see also [3] and [10]). Within the framework of this concept, UcP conducts fatty acid anion and return of protonated fatty acid (FA) enables proton transport across the membrane.…”

Thermoregulatory, carboxyatractylate‐sensitive uncoupling in heart and skeletal muscle mitochondria of the ground squirrel correlates with the level of free fatty acids

“…This and some other observations (for reviews, see refs. [2] and [6]) indicate that fatty acid induced, ATMADP-antiporter-mediated uncoupling is involved in thermoregulatory responses of warmblooded animals.…”

Possible role of avian uncoupling protein in down‐regulating mitochondrial superoxide production in skeletal muscle of fasted chickens

“…5. If one accepts Skulachev's hypothesis [37], which assumes translocation of FFA anions by inner membrane proteins (Fig. 5A), FFA-mediated uncoupling could reduce mitochondrial superoxide production attributable to the action of adenine nucleotide translocator (ANT) and UCP.…”