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Uncoupling Protein-3 (UCP3): a Mitochondrial Carrier in Search of a Function

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Uncoupling Protein-3 (UCP3): a Mitochondrial Carrier in Search of a Function International Journal of Obesity (1999) 23, Suppl 6, S43±S45 ß 1999 Stockton Press All rights reserved 0307±0565/99 $12.00 http://www.stockton-press.co.uk/ijo Uncoupling protein-3 (UCP3): A mitochondrial carrier in search of a function BB Lowell1* 1Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA UCP3 is a mitochondrial protein with high homology to the established uncoupling protein, UCP1. Its high degree of homology to UCP1 suggests that UCP3 may be a true uncoupling protein. Preliminary biochemical studies are consistent with UCP3 having uncoupling activity. However, detailed functional studies are required to understand the true biochemical and physiological purpose of UCP3. These efforts should be aided by identi®cation of humans with inactivating mutations and=or the generation of gene knockout mice lacking UCP3. Keywords: brown adipose tissue; skeletal muscle; adipose tissue; UCP3 isoforms Introduction ( 71% identical at the amino acid level). UCP3 is much less homologous to other members of the mitochondrial carrier super family: oxoglutarate car- Uncoupling protein-1 (UCP1) is a brown fat-speci®c, rier ( 32% identical), citrate carrier ( 25% identi- mitochondrial inner membrane protein with proton cal), carnitine carrier ( 25% identical), phosphate transport activity. This activity uncouples fuel con- carrier ( < 25% identical) and ADP=ATP carrier sumption from the conversion of ADP to ATP, ( < 25% identical). Based upon the high homology thereby releasing stored energy as heat. In rodents, of UCP3 with UCP1, compared to its lower homology UCP1 activity and brown fat contribute importantly to with other members of the mitochondrial carrier whole body energy expenditure. In humans, however, family, it is predicted that UCP3 shares biochemical brown fat is less abundant, and may not play a functions with UCP1, including uncoupling activity. signi®cant role in regulating energy balance. In support of this view, it has been shown that Recently, two additional mitochondrial carriers with UCP3, like UCP1, decreases mitochondrial membrane high homology to UCP1 were molecularly cloned. In potential when expressed in yeast 3 and mammalian4 contrast with UCP1, UCP2 is expressed widely and cells. In contrast with this view, it has recently been UCP3 is expressed preferentially in skeletal muscle. shown by Bienengraeber et al 5 that simultaneous Preliminary studies suggest that UCP3, like UCP1, mutation of histidine residues H145 and H147 in has uncoupling activity. This continues to be an active UCP1 destroys proton transport activity as assessed area of investigation. If UCP3 is a genuine uncoupling using a reconstituted proteoliposome system. Muta- protein, then it is likely to be an important regulator of tion of only one of these histidine residues in UCP1 energy metabolism in humans. decreases proton transport activity by 90%. Of note, both histidines are absent from mouse and rat UCP3, and human UCP3 lacks the equivalent histidine, H145. Similarly, UCP2 lacks both histidine residues. Molecular cloning of UCP3 and This ®nding raises two possibilities: either UCP2 and predictions of function based on UCP3 do not transport protons or their mechanism of proton transport is different from that utilized by sequence homology UCP1. It should be noted that the mitochondrial carrier UCP3 was molecularly cloned initially by Boss et al,1 family in mammals has additional members of known and then shortly thereafter by Vidal-Puig et al 2 and function which have yet to be molecularly cloned. Gong et al.3 UCP3 is highly homologous to UCP1 These include the dicarboxylate carrier, the ornithine ( 57% identical at the amino acid level) and UCP2 carrier, the pyruvate carrier and the aspartate= glutamate carrier.6 These carriers have been bio- chemically puri®ed and studied in vitro using recon- *Correspondence: Bradford B. Lowell, MD, PhD, Division of stituted proteoliposome systems. Since these carriers Endocrinology, RN-320, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, USA. have not been molecularly cloned, and the precise Email: [email protected] biochemical function of UCP3 has yet to be Function of UCP3 BB Lowell S44 established, it is formally possible that UCP3 repre- sents one of these carriers. UCP3 mRNA expression UCP3 is expressed abundantly and preferentially in skeletal muscle in humans and rodents1±3 and in brown fat in rodents1±3 but not humans.1 UCP3 expression in muscle is markedly upregulated by starvation.3 The purpose of starvation-induced upre- gulation of UCP3 is unknown, and con¯icts with the notion that UCP3 positively regulates systemic energy expenditure, as energy expenditure decreases during starvation. It has been suggested that the starvation- induced increase in UCP3 is caused by elevated free fatty acids and somehow plays an important role in 7 their metabolism. This is an attractive hypothesis in Figure 1 Human UCP3 gene structure. Human UCP3 gene with that muscle is a major site of free fatty acid metabo- start codon (ATG), stop codons (TGAS for UCP3S and TGAL for UCP3L) and cleavage and polyA adenylation signals (AATAAAS lism, especially during starvation. However, as of yet 8 for UCP3S and AATAAAL for UCP3L) are shown above. Exons 0 there is no clear view regarding the role of UCP3 in are coded from 1±7. 3 untranslated regions for UCP3S and free fatty acid metabolism. UCP3L are shown as UTRS and UTRL, respectively. Schematic cDNAs are shown below the gene structure. On the bottom is the exact location of the splice donors and splice acceptors (large case letters refer to exon sequence, small case letters refer to intron sequence). Amino acids adjacent to the splice sites are UCP3 short form transcript shown below the nucleotide sequence. Unlike UCP1 and UCP2, human UCP3 mRNA exists as short and long-form transcripts, UCP3S and missing from UCP3S are encoded by exon 7. Of 18 UCP3L. UCP3S is predicted to encode a protein interest, a mutation in the ®rst base pair of the which lacks the last 37C-terminal residues of intron between exon 6 and 7 has been identi®ed.13 UCP3L. It has previously been established that This mutation destroys the splice donor site, prevent- 9 UCP1 has six transmembrane domains. Based upon ing UCP3L from being generated. Consequently, this homology of UCP3 to UCP1, UCP3S should lack most allele can only generate UCP3S. It was reported that of the 6th transmembrane domain as well as C- individuals heterozygous for this mutation have terminal sequence. The corresponding region in normal body weight. However, basal fatty acid oxida- UCP1, absent in UCP3S, is thought to participate in tion was reduced by 50% and respiratory quotient was purine nucleotide binding10,11 which inhibits UCP1 markedly increased in these individuals.13 These ®nd- uncoupling activity, therefore raising the possibility ings are consistent with the view that UCP3S has that UCP3S has increased activity. Alternatively, it is decreased activity and that UCP3 plays an important possible that mature UCP3S protein is unstable and role in free fatty acid metabolism. However, a more does not exist. In summary, it is presently unknown detailed analysis of individuals with this mutations, as whether UCP3S exists as a mature protein, and=or well as a determination of functional properties of whether its activity is increased or decreased with UCP3S vs UCP3L protein is required to fully under- respect to UCP3L. stand the signi®cance of these observations. References UCP3 gene structure and basis for 1 Boss O, Samec S, Paoloni-Giacobino A, Rossier C, Dulloo A, Seydoux J, Muzzin P, Giacobino JP. Uncoupling protein-3: a short form transcript new member of the mitochondrial carrier family with tissue- speci®c expression. FEBS Lett 1997; 408: 39±42. 2 Vidal-Puig A, Solanes G, Grujic D, Flier JS, Lowell BB. The human UCP3 gene consists of seven exons UCP3: an uncoupling protein homologue expressed preferen- spanning 8.5 kb and is located on chromosome 11 tially and abundantly in skeletal muscle and brown adipose (11q13), adjacent to UCP2.8,12 UCP3 transcript is tissue. Biochem Biophys Res Commun 1997; 235: 79±82. S 3 Gong DW, He Y, Karas M, Reitman M. Uncoupling protein-3 generated when a cleavage and polyadenylation signal is a mediator of thermogenesis regulated by thyroid hormone, (AATAAA) located in intron 6 prematurely termi- beta3-adrenergic agonists, and leptin. J Biol Chem 1997; 272: nates message elongation (Figure 1). The 37 residues 24129±24132. Function of UCP3 BB Lowell S45 4 Boss O, Samec S, Kuhne F, Bijlenga P, Assimacopoulos- 10 Murdza-Inglis DL, Modriansky M, Patel HV, Woldegiorgis G, Jeannet F, Seydoux J, Giacobino JP, Muzzin P. Uncoupling Freeman KB, Garlid KD. A single mutation in uncoupling protein-3 expression in rodent skeletal muscle is modulated by protein of rat brown adipose tissue mitochondria abolishes food intake but not by changes in environmental temperature. GDP sensitivity of H transport. J Biol Chem 1994; 269: J Biol Chem 1998; 273: 5±8. 7435±7438. 5 Bienengraeber M, Echtay KS, Klingenberg M. H transport by 11 Bouillaud F, Arechaga I, Petit PX, Raimbault S, Levi-Meyr- uncoupling protein (UCP-1) is dependent on a histidine pair, ueis C, Casteilla L, Laurent M, Rial E, Ricquier D. A sequence absent in UCP-2 and UCP-3. Biochemistry 1998; 37:3±8. related to a DNA recognition element is essential for the 6 Palmieri F. Mitochondrial carrier proteins. FEBS Lett 1994; inhibition by nucleotides of proton transport through the 346: 48±54. mitochondrial uncoupling protein. Embo J 1994; 13: 1990± 7 Weigle DS, Selfridge LE, Schwartz MW, Seeley RJ, Cum- 1997. mings DE, Havel PJ, Kuijper JL, BeltrandelRio H. Elevated 12 Boss O, Giacobino JP, Muzzin P. Genomic structure of free fatty acids induce uncoupling protein 3 expression in uncoupling protein-3 (UCP3) and its assignment to chromo- muscle: a potential explanation for the effect of fasting.
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