The mitochondrial uncoupling proteins
© BioMed Central Ltd 2002
Published: 29 November 2002
The uncoupling proteins (UCPs) are transporters, present in the mitochondrial inner membrane, that mediate a regulated discharge of the proton gradient that is generated by the respiratory chain. This energy-dissipatory mechanism can serve functions such as thermogenesis, maintenance of the redox balance, or reduction in the production of reactive oxygen species. Some UCP homologs may not act as true uncouplers, however, and their activity has yet to be defined. The UCPs are integral membrane proteins, each with a molecular mass of 31-34 kDa and a tripartite structure in which a region of around 100 residues is repeated three times; each repeat codes for two transmembrane segments and a long hydrophilic loop. The functional carrier unit is a homodimer. So far, 45 genes encoding members of the UCP family have been described, and they can be grouped into six families. Most of the described genes are from mammals, but UCP genes have also been found in fish, birds and plants, and there is also functional evidence to suggest their presence in fungi and protozoa. UCPs are encoded in their mature form by nuclear genes and, unlike many nuclear-encoded mitochondrial proteins, they lack a cleavable mitochondrial import signal. The information for mitochondrial targeting resides in the first loop that protrudes into the mitochondrial matrix; the second matrix loop is essential for insertion of the protein into the inner mitochondrial membrane. UCPs are regulated at both the transcriptional level and by activation and inhibition in the mitochondrion.
Gene organization and evolutionary history
Gene localization and structure
The structure of the Ucp1 gene is highly conserved in mouse, rat and human: six exons encompass the coding sequence, each exon encoding a transmembrane domain. The structures of Ucp2 and Ucp3 are similar to that of Ucp1, with six coding exons. Ucp2 and Ucp3 also have two or one additional non-translated 5' exons, giving eight and seven exons, respectively. A particular feature of the mouse and human Ucp2 genes is the presence in exon 2 of several ATG-translation initiation codons in-frame with an open reading frame for an unknown peptide of 36 amino acids (the Ucp2 coding sequence begins in exon 3). Unlike Ucp1 and Ucp2, the human Ucp3 gene is expressed as two splice variants generated by alternative splicing of the last intron; one transcript encodes the full-length protein (UCP3L), while the other encodes a truncated version (UCP3S) lacking the sixth transmembrane domain. This UCP3S variant is generated when a cleavage and polyadenylation signal (AATAAA), located in the last intron, terminates message elongation prematurely . BMCP1 and UCP4 have also been reported to have isoforms of varying lengths. The structure of the genes of plant UCPs is somewhat different; in Arabidopsis, for example, the UCP genes all contain nine exons . Arabidopsis AtUCP2 is located in chromosome 5.
Summary of the known members of the uncoupling protein family
Red sea bream
Characteristic structural features
The UCPs do not have an amino-terminal cleavable import sequence to drive their incorporation into mitochondria. A recent report  has shown that, in UCP1, the net positive charge of the first matrix loop resembles a targeting signal and that it can interact with hTom20, a receptor protein of the outer mitochondrial membrane import complex. UCP1 has two other binding sites for hTom20, in the second transmembrane domain and in the central matrix loop, but the one in the second matrix loop is the critical one for targeting and insertion into the inner membrane .
Mitochondrial transporters such as the UCPs show the general properties described for carriers, including high substrate specificity and low turnover numbers. Under patch-clamp conditions, however, UCP1 displays a channel conductance of 75 pS, which is too high for a carrier mode. Deletion of nine amino acids from the third matrix loop of UCP1 leads to a pore-like state in which molecules of at least 1,000 Da can permeate, suggesting that this UCP1 mutant acts more like a channel than a carrier. This dual behaviour, carrier and channel, has also been observed for many other carriers and could be an indication that carriers and channels have a common origin and share a basic mechanism of transport. From a structural point of view, it suggests that there is a hydrophilic translocation pathway in the core of the protein, access to which would be controlled by gates, as are found in channels . We have recently proposed that, in UCP1, the bundle formed by transmembrane α-helices constitutes a hydrophilic channel, while the loops contribute to the formation of the gates .
Localization and function
Over the last few years, proteins homologous to UCP1 have been described not only in other mammalian tissues but also in other organisms, including plants. Four new uncoupling proteins have been described in mammals. UCP2 is expressed in many tissues. UCP3 is expressed only in brown adipose tissue and skeletal muscle, and UCP4 and BMCP1 are present only in brain. The function of the UCPs other than UCP1 is not yet clear, but their wide distribution suggests that regulation of the efficiency of oxidative phosphorylation through physiological uncoupling may be a general strategy. There is evidence to suggest, however, that some UCP homologs may not be involved in physiological uncoupling (discussed below).
UCPs are generally strongly regulated at two levels: transcription of the gene and protein activity in the mitochondrion. As an example of transcriptional regulation, the level of Ucp1 mRNA rises in brown adipose tissue only 15 minutes after cold exposure. The 5' flanking region of the rat, mouse and human Ucp1 genes contain cis-acting elements including a potent 200-bp enhancer involved in tissue-specific expression and hormonal regulation . The enhancer is complex and contains response elements for cyclic AMP, retinoids, thyroid hormone, thiazolidinediones, and other regulators. The Ucp2 promoter does not contain the TATA box typical of many promoters but instead is GC-rich; it contains several potential binding motifs for transcription factors such as Sp1, AP-1, AP-2, the cyclic AMP response element binding protein (CREB) and the muscle regulator MyoD . Consensus binding motifs for the CCAAT box and the Y box have also been described in the Ucp2 promoter region. The Ucp2 gene is downregulated in cis at the translational level by an upstream open reading frame located in exon 2 . The expression of the Ucp3 gene in skeletal muscle is also under strict transcriptional regulation, but the molecular mechanism controlling its expression has not been fully established . In the proximal 5' flanking region of the Ucp3 gene, several potential binding sequences for regulatory factors, such as MyoD, another muscle regulator MEF2, peroxisome-proliferator-activated receptors and thyroid hormone receptors have been described.
The function, transport properties and regulation of other members of the UCP family are still being defined. It has been suggested that all the UCPs may respond to nucleotides and fatty acids in a similar way to UCP1 , but the physiological context in which UCP1 operates is unique (there is an acute noradrenergic control of the thermogenic activity) and thus the physiological regulation of other UCPs is likely to be different.
The uncoupling proteins form part of a superfamily of metabolite transporters of the mitochondrial inner membrane, which are mainly anion carriers (Figure 5). Investigation of the bioenergetic properties of the mitochondria of brown adipose tissue was initiated when it was observed that their permeability to anions such as chloride or bromide was unusually high. It was subsequently shown that UCP1 can transport a variety of anions, an observation that has frequently led to the suggestion that UCP1 is a hydroxyl anion transporter rather than a proton carrier . Its proposed activity as a fatty acid anion transporter would be in line with these observations .
UCP2 is the member of the family with the widest distribution among cell types , but its expression levels vary depending on the tissue and on the physiological situation. Since its discovery in 1997 , UCP2 has been shown to be involved in various cellular processes. The consensus is emerging that it probably has more than one function, which will depend on the physiological context. The phenotypes observed in Ucp2-/- knockout mice suggest that the wild-type UCP2 has an uncoupling activity in vivo: the animals are neither obese nor cold-sensitive but their macrophages produce more free radicals than wild-type macrophages, indicating a higher membrane potential . The result of this high production of reactive oxygen species (ROS) is that the animals are more resistant to infection. Another research group has shown that Ucp2-/- knockout mice also have higher than wild type ATP levels in the pancreatic islets of Langerhans, resulting in abnormally high insulin levels . Similarly, work with intact thymocytes from Ucp2-/- knockout mice has led to an estimate that UCP2 could be responsible for 50% of the resting proton leak . UCP2 expression is generally increased in situations of oxidative stress, in which circumstance UCP2 would protect cells by limiting mitochondrial ROS production and therefore preventing the onset of apoptosis . Macrophages respond to infection by lowering UCP2 levels and thus enhancing the production of ROS, which are used to fight infection. An interesting proposal has recently been put forward that UCP2 acts as a carrier for the superoxide anion, thus helping to decrease the mitochondrial concentration of ROS .
Several observations suggest that UCP2 could be involved in lipid metabolism. First, its expression is induced under starvation, when circulating fatty acid levels are elevated . Moreover, when adipocytes are stimulated by the hormone leptin, the levels of UCP2 and of enzymes involved in fatty acid oxidation increase. Thus, when lipolysis is stimulated by leptin, fatty acids are not exported to liver but are oxidized in the adipocyte . UCP2 could have a dual role in this process: it could trigger fat oxidation that is not coupled to energy-requiring processes, and/or it could prevent the oxidative damage usually produced under conditions of high lipid levels.
The expression of UCP3 is restricted to skeletal muscle and brown adipose tissue . The physiological role and transport activity of UCP3 is still a matter of debate, despite the large number of publications on the issue, but evidence suggests that it may not have a role in energy dissipation. In line with this idea, UCP3 levels increase during fasting, a situation where energy efficiency should be increased , and Ucp3-/- mice do not have altered whole-body metabolism , although at the cellular level they do show increased energetic efficiency . The induction of UCP3 in muscle during starvation has been considered to be a consequence of its role in handling lipids as fuels, similar to the situation for UCP2 . Two possible functions have been proposed. Although some authors argue that Ucp3 is a carrier of fatty acids that facilitates their efflux from the mitochondrial matrix to help to regenerate free coenzyme A , while others suggest that UCP3 could prevent lipid-induced oxidative damage . On the other hand, there are also indications that UCP3 has uncoupling activity. Firstly, transgenic mice overexpressing Ucp3 have been shown to have a higher resting oxygen consumption than wild-type mice, and although their muscle fibres maintain a contractile performance similar to that of wild-type animals, energy turnover is clearly higher in the mutants . Secondly, a recent paper has shown a correlation between the level of UCP3 expression, the rate of mitochondrial proton leakage and the success in weight loss of overweight women .
UCP4 and BMCP1 are distantly related UCP homologs that are expressed only in the brain. Their functions are not known, but they have been implicated in processes similar to those suggested for UCP2 and UCP3. The role of the plant uncoupling proteins is still being elucidated. Some of them (proteins from potato, Arabidopsis and cabbage) have been shown to respond when plants are subjected to cold stress, suggesting that they have a thermogenic role analogous to that of mammalian UCP1. These proteins have also been shown to reduce ROS generation, again showing a parallel with animal UCPs. Specific plant functions also involve UCP-mediated energy dissipation. During fruit ripening, heat is generated, and it had been previously thought that this thermogenesis was mainly due to the induction in the respiratory chain of the alternative oxidase. However, it has already been demonstrated in tomato and mango that UCPs play an essential role in this process .
The uncoupling-protein field is growing rapidly, with an almost continuous description of new family members. The discovery of UCPs in many different eukaryotic organisms suggests that the regulation of energetic efficiency through the physiological uncoupling of oxidative phosphorylation may be a common strategy developed early in evolution. The current avalanche of data on the UCP family do not allow us to outline a definite task for each family member; the situation is more complex than anticipated. The view that is slowly emerging is that while the main function of UCP1 is thermoregulation, UCP2 is involved in the control of ROS generation and UCP3 in the handling of lipids as fuels. Plant UCPs seem to have similar functions to the mammalian UCPs, but ascribing a role solely on the basis of sequence analysis would be premature. The example of UCP2 illustrates the need for a detailed investigation of each protein in its respective cellular context. The role of UCP2 in the physiology of macrophages, pancreatic β cells or white adipocytes is probably not the same. Clearly, defining the physiological regulation of the activity would help to clarify these issues.
Those studying the biochemistry of UCPs also have a lot of work ahead. There are still fundamental uncertainties about their transport mechanism, and thus they have been proposed to transport fatty acids, protons or superoxide ions. Are all UCPs 'true' uncoupling proteins, or are some of them metabolite carriers? How are these transporters organized so that they can readily switch from carrier mode to channel mode? No high-resolution structural data are yet available for any member of the mitochondrial carrier superfamily, and when this information becomes available it could prove a turning point in understanding the molecular basis of the transport mechanism, specificity and regulation of UCPs.
The scientific interest in this protein family can be easily understood. At the cellular level, their role in the control of ATP levels, redox balance, oxidative stress and apoptosis shows their importance. Disturbances in UCP function could underlie pathological states such as obesity, diabetes, inflammatory processes or cancer cachexia. Development of drugs that modulate the activity of the UCPs could one day become a new strategy for the treatment of these pathologies.
We thank Frédéric Bouillaud and Daniel Ricquier for their helpful comments on the manuscript. This work has been supported by a grant from the Spanish Ministry of Science and Technology (BIO99-0870). A.L. is supported by a grant from the Comunidad de Madrid.
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