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Dipartimento di Scienze Biologiche ed Ambientali, 082100, Benevento, Italy; and
* Department of Bioenergetics, A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119992, GSP-2, Russia
1Correspondence: A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119992, GSP-2, Russia. E-mail: skulach{at}belozersky.msu.ru
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ABSTRACT |
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 TOP ABSTRACT A MYSTERY OF NOVEL...HOW UCPs OPERATEHYPOTHESIS: THE INNER LEAFLET...SOME PREDICTIONS OF THE...REFERENCES |
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Key Words: uncoupling protein • mitochondria • lipid peroxide • anion carrier
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A MYSTERY OF NOVEL UCPs |
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TOPABSTRACTA MYSTERY OF NOVEL...HOW UCPs OPERATEHYPOTHESIS: THE INNER LEAFLET...SOME PREDICTIONS OF THE...REFERENCES |
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2
3
4
5
6
). For many years, UCP1 was regarded as a unique protein absolutely specific for brown fat. As to uncoupling in other tissues also clearly involved in additional oxygen consumption at low ambient temperature, it was suggested to be carried out by mitochondrial anion carriers, first of all ATP/ADP antiporter (ANT) and aspartate/glutamate antiporter (AGA) which perform the uncoupling function, like UCP1, in a fatty acid-dependent fashion (reviewed in ref 2
).
However, in 1997 two more proteins were discovered resembling UCP1 in their sequences, namely, UCP2 found in all mammalian tissues except parenchymal hepatocytes (7)
, and UCP3, which proved to be specific for skeletal muscles and brown fat (8)
. Two more representatives of the same family, called UCP4 and 5, were later revealed in brain (9
, 10)
. Moreover, AvUCP closely related to mammalian UCP2 and 3 was identified in birds (11
, 12)
.
Surprisingly, UCPs were also described in poikilothermic organisms, e.g., in fish (13)
and plants (14
, 15)
. Some indirect indications for existence of UCPs in an amoeba (16)
and a parasitic yeast (17)
were published. On the other hand, in genomes of Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila, no UCP orthologs were revealed (18)
. Animal UCP1, 2, 3, AvUCP, and plant UCPs proved to be induced by cold exposure of the organism (2
, 3
, 15
, 18
19
20
21
22
23
24
25
26
27)
, supporting the original idea of UCPs as thermoregulatory proteins. This function cannot be inherent in unicellular organisms like amoeba and yeast. Moreover, even for warm-blooded mammals, thermoregulation is hardly the only function of such novel members of the UCP family as UCP2, 3, 4, and 5. Their amounts are two or even three orders of magnitude lower than that of UCP1 (18
, 28)
. Therefore, it is hardly surprising that knockouts of UCP2 or UCP3 genes are without any measurable influence on the thermoregulatory parameters of mice (for review, see refs 3
, 19
, 29
).
In 1996 one of us suggested that even small decrease in mitochondrial proton motive force can strongly lower production of reaction oxygen species (ROS) by mitochondria (30)
. This suggestion was experimentally proved (31
, 32)
and it was assumed that such "mild" uncoupling mediated by UCP2 and 3 may be an antioxidant mechanism (2
, 20)
.
Later it was observed that knockout of UCP2 and 3 have really strong pro-oxidant effects whereas their superproduction greatly increases antioxidant capacity of the cell (33
34
35
36)
. Brand et al. reported that UCP3 knockout increased the oxidative damage to skeletal muscle mitochondrial proteins (37)
. On the other hand, UCP3 overexpression did not influence this parameter as if the normal UCP3 concentration in these mitochondria was sufficient to carry out its antioxidant function (37)
. It was also found that tert-butyl hydroperoxide, oleic, or linoleic acids, when added to the cell growth medium, induced UCP2 synthesis in parenchymal hepatocytes normally lacking this protein (38)
. The same occurred after in vivo administration of bacterial lipopolysaccharide (39)
or tumor necrosis factor (6)
causing strong ROS production in hepatocytes. All these effects seem to indicate the involvement of UCP2 and 3 in the cell antioxidant response (6)
. In line with this assumption, Lowell and co-workers (36)
reported an increase in the ROS level in skeletal muscles from UCP3 knockout mice.
Casteilla and co-workers (33)
have found that GDP, a UCP inhibitor, increases 
and production of H2O2 by mitochondria from brown fat, spleen, thymus, and nonparenchymal liver cells expressing UCP2. GDP was completely ineffective in mitochondria from parenchymal hepatocytes.
Horvath and co-workers succeeded in demonstrating a protective effect of UCP2 in various brain pathologies, e.g., alcohol-induced oxidative stress (40)
and neuronal injury (41)
. In brain the UCP2 level increases with age (42)
, which might be a mechanism preventing damage to this most important tissue under conditions of progressive oxidative stress accompanying aging.
The antioxidant activity of the novel UCPs proved to be too large to be explained solely by contribution of UCP2 and 3 to the mild uncoupling. Such a contribution should be limited by small amounts of these proteins in comparison to ATP/ADP antiporter (ANT) which, like UCP, can mediate uncoupling by free fatty acids, the most probable candidates for the role of the natural uncouplers (1
, 2
, 43
, 44)
. In line with the above reasoning, it was shown that knockout of one of two ANT isoenzymes (muscle-specific ANT1) results in a strong increase in ROS production by the muscle mitochondria (45)
. Thus, the antioxidant role of novel UCPs still awaits explanation.
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HOW UCPs OPERATE |
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TOPABSTRACTA MYSTERY OF NOVEL...HOW UCPs OPERATEHYPOTHESIS: THE INNER LEAFLET...SOME PREDICTIONS OF THE...REFERENCES |
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, 46)
. Comparison of UCPs with ANT is especially interesting. Both ANT and UCP 1) have the same domain compositions, 2) are imported by mitochondria with no cleavable amino-terminal sequence involved, 3) bind purine nucleotides in their anionic forms, free fatty acids being able to compete with nucleotide, and 4) mediate the fatty acid-induced H+ conductance through the inner mitochondrial membrane; this effect is inhibited by nucleotides (1
, 20
, 44)
. UCP1 was studied in detail. It was found that UCP1 is competent in the transport of monovalent anions such as fatty acids, Cl-, NO3-, etc. (47
, 48)
. The transport rate and affinity proved to depend on hydrophobicity of the anion transported. The affinity of anions to UCP1 increases with their hydrophobicity (Cl-, 0.14 M; hexanesulfonate, 12 mM; undecanesulfonate, 12 µM; laurate, 8 µM; oleate, 5 µM). As to Vmax, it shows an optimum in the hydrophobic region: 9.0, 23.5, 37.6, 22.0, and 16.0 nmol/mg UCP1 x min for Cl-, hexanesulfonate, undecanesulfonate, laurate, and oleate, respectively (48)
. Undecanesulfonate was found to be a competitive inhibitor of laurate-induced uncoupling mediated by UCP1. Both laurate and undecanesulfonate were competitive inhibitors of Cl- transport (49
, 50)
.
All the above observations confirmed the hypothesis of the fatty acid cycle postulated by one of us as early as 1988 (1
, 44)
. The scheme in question is shown in the left part of Fig. 1
. It assumes that UCP1, like ANT, AGA, and some other mitochondrial anion carriers, facilitates an efflux of fatty acid anions that move electrophoretically in the field generated by the respiratory chain (mitochondrial matrix negative). When they appeared in the outer leaflet of the inner mitochondrial membrane, the fatty acid anions were protonated by H+ ions of the intermembrane space. Then protonated forms of fatty acids return to the inner leaflet by a flip-flop mechanism, crossing the phospholipid bilayer regions of the membrane. In the inner leaflet, fatty acids are deprotonated, releasing H+ ions to the matrix space.
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Later, an alternative explanation for role of fatty acids was put forward by Winkler and Klingenberg (51)
, who suggested that a fatty acid molecule is fixed inside the UCP protein, facilitating by its carboxylic group the H+ translocation via UCP. This scheme fails to explain many features of UCP, including effects of Cl- and undecanesulfonate, as well as the observation by Wojtczak et al. that only those fatty acid derivatives that can easily penetrate a phospholipid bilayer in their protonated forms can uncouple at low concentrations (52)
.
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HYPOTHESIS: THE INNER LEAFLET OF MITOCHONDRIAL MEMBRANE IS RIDDED OF LIPID PEROXIDES BY MEANS OF UCPs |
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TOPABSTRACTA MYSTERY OF NOVEL...HOW UCPs OPERATEHYPOTHESIS: THE INNER LEAFLET...SOME PREDICTIONS OF THE...REFERENCES |
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. In fact, it extends the fatty acid cycle scheme (1
, 44)
to anions of fatty acid peroxides, assuming that they can, like nonoxidized fatty acid anions, alkyl sulfonates, or Cl-, be electrophoretically translocated by UCP from the inner to the outer membrane leaflet. If that is the case, fatty acid peroxides are concentrated in the outer leaflet, the inner one being rid of them. Such an effect is a direct consequence of the fact that the chemical structure of fatty acid peroxides, in contrast to that of intact fatty acids, should be unfavorable for flip-flop via phospholipid bilayer (see below). Thus, peroxides translocated to the outer leaflet in a UCP-mediated manner will remain in this leaflet whereas the pool of these compounds in the inner leaflet will be exhausted.
It should be stressed that the same effect will also occur within the framework of the alternative Winkler–Klingenberg concept (51)
, assuming that the H+-translocating and anion-translocating activities of UCP are carried out by two different mechanisms. In this case, fatty acid peroxides can be transported by the anion-translocating machinery involved in efflux of Cl-, undecanesulfonate and other anions.
Our hypothesis accounts for why the amounts of the novel UCPs are so low. This is a consequence of the fact that concentrations of their substrates (fatty acid peroxides) are also low. The scheme also explains very recent results of the Brand’s group (53)
. It was found that O2.- and H2O2 produced by xanthine and xanthine oxidase outside mitochondria cause some uncoupling that was specifically abolished by the matrix-targeted antioxidants (CoQ and vitamin E derivatives containing cationic triphenylphosphonium residue, see refs 54
55
56
). Within the framework of our hypothesis, the above antioxidants, being electrophoretically accumulated in the inner membrane leaflet, operate as scavengers of lipid peroxides in this leaflet. It is remarkable that nigericin and phosphate were always present in Brand’s experiments. These compounds are known to convert pH to (1)
and therefore must be favorable for uncoupling if an anion (here, a fatty acid peroxide) is electrophoretically extruded from mitochondria (the 
pH conversion; see ref 1
). In their preceding paper, Brand and co-workers showed that xanthine + xanthine oxidase uncoupling required fatty acids and does not occur in skeletal muscle mitochondria from the UCP3 knockout mice or when UCP was inhibited by GDP (28)
. The authors also found that extramitochondrially produced ROS really enter the matrix, inactivating the matrix-localized aconitase (53)
. Within the framework of our scheme, external xanthine oxidase-generated ROS induce phospholipid peroxidation not only in the outer but also in the inner membrane leaflet. Peroxidized phospholipids could be split by a phospholipase to form free fatty acid peroxides which were pumped out by UCP from the inner to outer leaflet.
It is noteworthy that ANT and other mitochondrial anion carriers, in contrast to UCPs, cannot translocate monoanions less hydrophobic than fatty acids. One may speculate that anion binding cationic amino acid residues are localized closer to the surface of the protein in the case of UCPs than of other anion carriers so that fatty acid peroxides can still be bound in spite of the presence of an additional hydrophilic residue. In this connection, we would like to remember that dependence of Vmax of the UCP1 anion transport upon anion hydrophobicity shows such an optimum that laurate and undecanesulfonate are transported better than Cl- and oleate (see above). This lends probability to the assumption that oleate peroxide, being less hydrophobic than oleate, will be translocated faster than oleate.
Quite recently, Jezek and co-workers (57)
have reported that 
-6-polyunsaturated fatty acids are much better activators of the UCP2 and UCP3 than less unsaturated or saturated fatty acids. In fact, Km for C20:3 -6 fatty acid proved to be more than 20-fold lower than for myristic acid. This observation is obviously in line with our hypothesis.
If our hypothesis is right, a question arises as to why transfer of fatty acid peroxides from the inner to outer leaflet has a favorable biological effect. To answer this question, we should compare the composition of mitochondrial matrix and intermembrane space. It seems obvious that the metabolic pattern of matrix is much more complicated and important for the cell than that of the intermembrane space. In contrast to the intermembrane space, matrix contains DNA and RNAs and far more numerous enzymes, catalyzing, e.g., such a crucial metabolic system as the Krebs cycle. Some of the above systems are very sensitive to ROS. For instance, aconitase, catalyzing the initial step of the Krebs cycle, is one of the most O2.--sensitive proteins in the cell (58
, 59)
. Moreover, DNA polymerase 
, the only polymerase active in mitochondria, is prone to oxidative damage (60)
. ANT seems to have ROS-sensitive -SH groups on its matrix surface, and their modification apparently results in opening of the permeability transition pore (61)
. As to the intermembrane space, there are no nucleic acids or complex metabolic cycles and the number of enzymes is very limited; some are not only ROS resistant, but even operate as ROS scavengers (cytochrome c and, in yeast, cytochrome c peroxidase) (62)
.
Peroxidation of lipids initiates chain reactions producing very aggressive oxidants (63)
. After electrophoretic translocation by UCPs, fatty acid peroxides form these oxidants on the outer surface of the membrane so that components of the intermembrane space, rather than those of the matrix, appear to be their targets. In this way, the matrix targets (first of all, mtDNA) can be defended. How important such defense may be is illustrated by the fact that longevity of mammals shows reverse correlation with degree of oxidation of mtDNA. The mtDNA oxidation was in turn proportional to the rates of mitochondrial ROS production and degrees of mitochondrial fatty acid unsaturation (64)
. The importance of the antioxidant defense of the matrix space is well illustrated by observations that knockouts of genes of cytosolic superoxide dismutase result in mild nonlethal phenotypes whereas the gene of the matrix superoxide dismutase gives rise to a neonatal lethal phenotype characterized by mtDNA oxidative damage as well as the respiratory chain and Krebs cycle abnormalities (65
66
67
68)
. In line with the above reasoning, Santos et al. reported recently (69)
that addition of H2O2 to fibroblasts resulted in oxidation of mtDNA which was partially repaired during 6 h. Nuclear DNA remained completely resistant. Cell sorting experiments revealed persistent mtDNA damage at 24 h only in the fraction of cells with low mitochondrial membrane potential.
It should be mentioned that anions of fatty acid peroxides when they appear in the outer leaflet cannot come back via UCP until (inside negative) is present. As to the protonated peroxides, their flip-flop is assumed to be slower than the UCP-mediated extrusion. Such an assumption seems probable since fatty acid derivatives having, besides a carboxylic group, an –OH residue show, according to Wojtczak et al. (52)
, a much lower flip-flop rate than nonmodified fatty acids. It seems that addition of –OOH instead of –OH will have a similar effect.
A question arises as to what happens with fatty acid peroxides accumulated in the outer leaflet of the inner membrane. One possibility is that they are attacked by the phospholipid hydroperoxide glutathione peroxidase, which is known to reduce peroxides in fatty acid residues of phospholipids and in a wide range of other lipid molecules (71)
. If this enzyme is present in the intermembrane space (for some indications, see refs 70
, 72
), fatty acid peroxides (LOOH) might be reduced to LOH just in the outer leaflet of the inner membrane. If this is not the case, the cytosolic phospholipid hydroperoxide glutathione peroxidase might be involved provided that fatty acid peroxides are translocated from the inner to the outer mitochondrial membrane via the membrane contacting sites or by a fatty acid binding protein. It also seems possible that cytochrome c in the intermembrane space converts LOOH to LO·, an event followed by a break in the fatty acid hydrocarbon chain (73)
. Such a mechanism does not requite translocation of LOOH from the inner to the outer membrane.
It is quite clear that the probability of peroxidation of fatty acids must increase with increase in their concentration. This might explain why levels of UCP2 and 3 rise when lipids are mobilized as a fuel, e.g., on fasting (for reviews, see refs 20
, 74
), cooling (see above), or thyroid hormone-induced hypermetabolism (75
76
77)
. On the other hand, they may contribute to heat production when low temperature becomes a challenge for the very existence of the organism. This may be a manifestation of a general physiological principle that, under critical conditions, all the possible mechanisms favorable for survival should be activated.
The above concept does not assume that fatty acid peroxide translocation is the only antioxidant mechanism inherent in UCPs. It seems possible that under some conditions they are also involved in the mild uncoupling. This might take place in tissues where UCPs make measurable contribution to the mitochondrial H+ conductance in the resting state (see, e.g., ref 36
).
One more UCP function related to the ability of these proteins to translocate fatty acid anions was recently postulated by Himms-Hagen and Harper (78)
. These authors suggested that excess of free fatty acids may result in a situation when all the mitochondrial CoA pool is converted to acyl CoA. This should inhibit other CoA-dependent processes. To solve the problem, fatty acyl CoA is assumed to be hydrolyzed by mitochondrial thioesterase to form free fatty acid anion and CoA, the former being electrophoretically exported by UCPs. In line with this assumption, it was observed (79)
that fenofibrate, a hypolipidemic drug, increased levels of both UCP3 and thioesterase. Thus, at least under some conditions, the Himms-Hagen and Harper hypothesis seems to be realistic. In particular, it explains how mitochondrion can deal with free fatty acids released due to thioesterase activity in matrix where there is no enzyme converting fatty acid and CoA to acylCoA. However, it should be taken into account that steady transmembrane gradient of free nonoxidized fatty acids cannot be maintained by UCPs, since it is impossible to avoid protonation of fatty acid anions on the outer surface of the inner membrane and subsequent downhill flip-flop of protonated fatty acids from the outer to inner membrane leaflet. Moreover, the hypothesis in question fails to explain potent antioxidant effects of UCP2 and UCP3 (see above).
Multifunctionality of UCPs may explain why five different representatives of this protein family coexist in the same mammalian organism. It is noteworthy that UCP2 and UCP3 differ in the activator (CoQ derivatives) and inhibitor (ATP and ADP) patterns (35
, 80
81
82)
. These facts may point to different relationships between alternative UCP functions in various UCPs.
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SOME PREDICTIONS OF THE HYPOTHESIS |
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TOPABSTRACTA MYSTERY OF NOVEL...HOW UCPs OPERATEHYPOTHESIS: THE INNER LEAFLET...SOME PREDICTIONS OF THE...REFERENCES |
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for peroxide translocation should entail the pH transition, which may result in some uncoupling if pH is discharged either by nigericin or by phosphate, H+-symporter. must entail equilibration of the fatty acid peroxide levels between the two membrane leaflets and, as a consequence, strongly increase oxidative damage to mtDNA, aconitase, and other matrix ROS targets.
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ACKNOWLEDGMENTS |
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Received for publication March 10, 2003. Accepted for publication May 8, 2003.
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REFERENCES |
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TOPABSTRACTA MYSTERY OF NOVEL...HOW UCPs OPERATEHYPOTHESIS: THE INNER LEAFLET...SOME PREDICTIONS OF THE...REFERENCES |
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-6 polyunsaturated fatty acids and inhibitory purine nucleotides are high affinity ligands for novel mitochondrial uncoupling proteins UCP2 and UCP3. J. Biol. Chem. 218,20771-20969
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