ID UCP3_HUMAN Reviewed; 312 AA. AC P55916; O60475; Q96HL3; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1997, sequence version 1. DT 04-NOV-2026, entry version 201. DE RecName: Full=Putative mitochondrial transporter UCP3 {ECO:0000305}; DE AltName: Full=Solute carrier family 25 member 9; DE AltName: Full=Uncoupling protein-3 {ECO:0000303|PubMed:9180264}; DE Short=UCP 3; GN Name=UCP3 {ECO:0000303|PubMed:9180264, ECO:0000312|HGNC:HGNC:12519}; GN Synonyms=SLC25A9 {ECO:0000312|HGNC:HGNC:12519}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Skeletal muscle; RX PubMed=9180264; DOI=10.1016/s0014-5793(97)00384-0; RA Boss O., Samec S., Paoloni-Giacobino A., Dulloo A., Seydoux J., Rossier C., RA Muzzin P., Giacobino J.-P.; RT "Uncoupling protein-3: a new member of the mitochondrial carrier family RT with tissue-specific expression."; RL FEBS Lett. 408:39-42(1997). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS UCP3L AND UCP3S). RX PubMed=9325252; DOI=10.1074/jbc.272.41.25433; RA Solanes G., Vidal-Puig A., Grujic D., Flier J.S., Lowell B.B.; RT "The human uncoupling protein-3 gene. Genomic structure, chromosomal RT localization, and genetic basis for short and long form transcripts."; RL J. Biol. Chem. 272:25433-25436(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM UCP3L), AND TISSUE SPECIFICITY. RX PubMed=9196039; DOI=10.1006/bbrc.1997.6740; RA Vidal-Puig A., Solanes G., Grujic D., Flier J.S., Lowell B.B.; RT "UCP3: an uncoupling protein homologue expressed preferentially and RT abundantly in skeletal muscle and brown adipose tissue."; RL Biochem. Biophys. Res. Commun. 235:79-82(1997). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=9305858; DOI=10.1074/jbc.272.39.24129; RA Gong D.-W., He Y., Karas M., Reitman M.; RT "Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid RT hormone, beta3-adrenergic agonists, and leptin."; RL J. Biol. Chem. 272:24129-24132(1997). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=9498661; DOI=10.1007/s001250050897; RA Urhammer S.A., Dalgaard L.T., Soerensen T.I.A., Tybjaerg-Hansen A., RA Echwald S.M., Andersen T., Clausen J.O., Pedersen O.; RT "Organisation of the coding exons and mutational screening of the RT uncoupling protein 3 gene in subjects with juvenile-onset obesity."; RL Diabetologia 41:241-244(1998). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=10958796; DOI=10.1074/jbc.m005713200; RA Esterbauer H., Oberkofler H., Krempler F., Strosberg A.D., Patsch W.; RT "The uncoupling protein-3 gene is transcribed from tissue-specific RT promoters in humans but not in rodents."; RL J. Biol. Chem. 275:36394-36399(2000). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Skeletal muscle; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=11171965; DOI=10.1073/pnas.98.4.1416; RA Echtay K.S., Winkler E., Frischmuth K., Klingenberg M.; RT "Uncoupling proteins 2 and 3 are highly active H(+) transporters and highly RT nucleotide sensitive when activated by coenzyme Q (ubiquinone)."; RL Proc. Natl. Acad. Sci. U.S.A. 98:1416-1421(2001). RN [9] RP FUNCTION. RX PubMed=11707458; DOI=10.1074/jbc.m109736200; RA Cadenas S., Echtay K.S., Harper J.A., Jekabsons M.B., Buckingham J.A., RA Grau E., Abuin A., Chapman H., Clapham J.C., Brand M.D.; RT "The basal proton conductance of skeletal muscle mitochondria from RT transgenic mice overexpressing or lacking uncoupling protein-3."; RL J. Biol. Chem. 277:2773-2778(2002). RN [10] RP FUNCTION. RX PubMed=12670931; DOI=10.1074/jbc.m212850200; RA Zackova M., Skobisova E., Urbankova E., Jezek P.; RT "Activating omega-6 polyunsaturated fatty acids and inhibitory purine RT nucleotides are high affinity ligands for novel mitochondrial uncoupling RT proteins UCP2 and UCP3."; RL J. Biol. Chem. 278:20761-20769(2003). RN [11] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=12734183; DOI=10.1074/jbc.m302126200; RA Jaburek M., Garlid K.D.; RT "Reconstitution of recombinant uncoupling proteins: UCP1, -2, and -3 have RT similar affinities for ATP and are unaffected by coenzyme Q10."; RL J. Biol. Chem. 278:25825-25831(2003). RN [12] RP FUNCTION. RX PubMed=21775425; DOI=10.1074/jbc.m110.216044; RA De Marchi U., Castelbou C., Demaurex N.; RT "Uncoupling protein 3 (UCP3) modulates the activity of Sarco/endoplasmic RT reticulum Ca2+-ATPase (SERCA) by decreasing mitochondrial ATP production."; RL J. Biol. Chem. 286:32533-32541(2011). RN [13] RP INTERACTION WITH HAX1. RX PubMed=26915802; DOI=10.1016/j.bbrc.2016.02.075; RA Hirasaka K., Mills E.M., Haruna M., Bando A., Ikeda C., Abe T., Kohno S., RA Nowinski S.M., Lago C.U., Akagi K., Tochio H., Ohno A., Teshima-Kondo S., RA Okumura Y., Nikawa T.; RT "UCP3 is associated with Hax-1 in mitochondria in the presence of calcium RT ion."; RL Biochem. Biophys. Res. Commun. 472:108-113(2016). RN [14] RP FUNCTION. RX PubMed=36114012; DOI=10.1002/1873-3468.14494; RA Codella R., Alves T.C., Befroy D.E., Choi C.S., Luzi L., Rothman D.L., RA Kibbey R.G., Shulman G.I.; RT "Overexpression of UCP3 decreases mitochondrial efficiency in mouse RT skeletal muscle in vivo."; RL FEBS Lett. 0:0-0(2022). RN [15] RP VARIANT OBESITY ILE-102. RX PubMed=9769326; DOI=10.1172/jci4115; RA Argyropoulos G., Brown A.M., Willi S.M., Zhu J., He Y., Reitman M., RA Gevao S.M., Spruill I., Garvey W.T.; RT "Effects of mutations in the human uncoupling protein 3 gene on the RT respiratory quotient and fat oxidation in severe obesity and type 2 RT diabetes."; RL J. Clin. Invest. 102:1345-1351(1998). RN [16] RP VARIANT OBESITY TRP-70. RA Brown A.M., Willi S.M., Argyropoulos G., Garvey W.T.; RT "A novel missense mutation, R70W, in the human uncoupling protein 3 gene in RT a family with type 2 diabetes."; RL Hum. Mutat. 13:506-506(1999). CC -!- FUNCTION: Putative transmembrane transporter that plays a role in CC mitochondrial metabolism via an as yet unclear mechanism CC (PubMed:21775425, PubMed:36114012). Originally, this mitochondrial CC protein was thought to act as a proton transmembrane transporter from CC the mitochondrial intermembrane space into the matrix, causing proton CC leaks through the inner mitochondrial membrane, thereby uncoupling CC mitochondrial membrane potential generation from ATP synthesis CC (PubMed:11171965, PubMed:12670931, PubMed:12734183, PubMed:9305858). CC However, this function is controversial and uncoupling may not be the CC function, or at least not the main function, but rather a consequence CC of more conventional metabolite transporter activity (PubMed:11707458). CC {ECO:0000269|PubMed:11171965, ECO:0000269|PubMed:11707458, CC ECO:0000269|PubMed:12670931, ECO:0000269|PubMed:12734183, CC ECO:0000269|PubMed:21775425, ECO:0000269|PubMed:36114012, CC ECO:0000269|PubMed:9305858}. CC -!- ACTIVITY REGULATION: The proton transporter activity is activated by CC fatty acids (in vitro) (PubMed:11171965). The proton transporter CC activity is inhibited by ATP and ADP (in vitro) (PubMed:11171965). The CC effect of Ubiquinone/coenzyme Q10 on the proton transporter activity in CC reconstituted membranes is unclear (in vitro) (PubMed:11171965, CC PubMed:12734183). {ECO:0000269|PubMed:11171965, CC ECO:0000269|PubMed:12734183}. CC -!- SUBUNIT: Interacts with HAX1; the interaction is direct and calcium- CC dependent. {ECO:0000269|PubMed:26915802}. CC -!- INTERACTION: CC P55916; P03495: NS; Xeno; NbExp=2; IntAct=EBI-9116865, EBI-2548993; CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane CC {ECO:0000250|UniProtKB:P56501}; Multi-pass membrane protein CC {ECO:0000255}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=UCP3L {ECO:0000303|PubMed:9325252}; CC IsoId=P55916-1; Sequence=Displayed; CC Name=UCP3S {ECO:0000303|PubMed:9325252}; CC IsoId=P55916-2; Sequence=VSP_003271; CC Name=3; CC IsoId=P55916-3; Sequence=VSP_003270; CC -!- TISSUE SPECIFICITY: Only in skeletal muscle and heart (PubMed:9305858). CC Also expressed in white and brown adipose tissues (PubMed:9305858). Is CC more expressed in glycolytic than in oxidative skeletal muscles. CC {ECO:0000269|PubMed:9196039, ECO:0000269|PubMed:9305858}. CC -!- INDUCTION: Up-regulated by beta3-adrenergic stimulation, starvation, CC glucocorticoids and leptin. {ECO:0000269|PubMed:9305858}. CC -!- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by CC an increase of body weight beyond the limitation of skeletal and CC physical requirements, as the result of excessive accumulation of body CC fat. {ECO:0000269|PubMed:9769326, ECO:0000269|Ref.16}. Note=The gene CC represented in this entry may be involved in disease pathogenesis. CC -!- SIMILARITY: Belongs to the mitochondrial carrier (TC 2.A.29) family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAC51785.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U84763; AAC51367.1; -; mRNA. DR EMBL; U82818; AAC51356.1; -; mRNA. DR EMBL; AF001787; AAC51369.1; -; mRNA. DR EMBL; AF011449; AAC51767.1; -; mRNA. DR EMBL; AF012202; AAC51785.1; ALT_INIT; Genomic_DNA. DR EMBL; AF012197; AAC51785.1; JOINED; Genomic_DNA. DR EMBL; AF012198; AAC51785.1; JOINED; Genomic_DNA. DR EMBL; AF012199; AAC51785.1; JOINED; Genomic_DNA. DR EMBL; AF012200; AAC51785.1; JOINED; Genomic_DNA. DR EMBL; AF012201; AAC51785.1; JOINED; Genomic_DNA. DR EMBL; AF026958; AAC18822.1; -; Genomic_DNA. DR EMBL; AF026956; AAC18822.1; JOINED; Genomic_DNA. DR EMBL; AF026957; AAC18822.1; JOINED; Genomic_DNA. DR EMBL; AF050113; AAG02284.1; -; Genomic_DNA. DR EMBL; BC008392; AAH08392.1; -; mRNA. DR CCDS; CCDS44677.1; -. [P55916-2] DR CCDS; CCDS8229.1; -. [P55916-1] DR PIR; JC5522; JC5522. DR RefSeq; NP_003347.1; NM_003356.4. [P55916-1] DR RefSeq; NP_073714.1; NM_022803.3. [P55916-2] DR RefSeq; XP_047283475.1; XM_047427519.1. [P55916-1] DR AlphaFoldDB; P55916; -. DR SMR; P55916; -. DR BioGRID; 113199; 15. DR FunCoup; P55916; 212. DR IntAct; P55916; 2. DR NDEx; IQUERY-CP-UCP3; 3 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000323740; -. DR TCDB; 2.A.29.3.5; the mitochondrial carrier (mc) family. DR GlyCosmos; P55916; 1 site, 1 glycan. DR GlyGen; P55916; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P55916; -. DR PhosphoSitePlus; P55916; -. DR BioMuta; UCP3; -. DR PaxDb; 9606-ENSP00000323740; -. DR PeptideAtlas; P55916; -. DR Antibodypedia; 4388; 324 antibodies from 37 providers. DR DNASU; 7352; -. DR Ensembl; ENST00000314032.9; ENSP00000323740.4; ENSG00000175564.14. [P55916-1] DR Ensembl; ENST00000426995.2; ENSP00000392143.2; ENSG00000175564.14. [P55916-2] DR GeneID; 7352; -. DR KEGG; hsa:7352; -. DR MANE-Select; ENST00000314032.9; ENSP00000323740.4; NM_003356.4; NP_003347.1. DR UCSC; uc001our.4; human. [P55916-1] DR AGR; HGNC:12519; -. DR ClinPGx; PA37166; -. DR CTD; 7352; -. DR DisGeNET; 7352; -. DR GeneCards; UCP3; -. DR HGNC; HGNC:12519; UCP3. DR HPA; ENSG00000175564; Group enriched (skeletal muscle, tongue). DR MalaCards; UCP3; -. DR MIM; 601665; phenotype. DR MIM; 602044; gene. DR OpenTargets; ENSG00000175564; -. DR VEuPathDB; HostDB:ENSG00000175564; -. DR eggNOG; KOG0753; Eukaryota. DR GeneTree; ENSGT00940000161030; -. DR HOGENOM; CLU_015166_14_2_1; -. DR InParanoid; P55916; -. DR OMA; AACMVTH; -. DR OrthoDB; 448427at2759; -. DR PAN-GO; P55916; 6 GO annotations based on evolutionary models. DR PhylomeDB; P55916; -. DR PathwayCommons; P55916; -. DR Reactome; R-HSA-167826; The fatty acid cycling model. DR SignaLink; P55916; -. DR SIGNOR; P55916; -. DR Agora; ENSG00000175564; -. DR BioGRID-ORCS; 7352; 15 hits in 1150 CRISPR screens. DR GeneWiki; UCP3; -. DR GenomeRNAi; 7352; -. DR Pharos; P55916; Tbio. DR PRO; PR:P55916; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; P55916; protein. DR Bgee; ENSG00000175564; Expressed in gastrocnemius and 180 other cell types or tissues. DR ExpressionAtlas; P55916; baseline and differential. DR GO; GO:0005743; C:mitochondrial inner membrane; ISS:UniProtKB. DR GO; GO:0005739; C:mitochondrion; HTP:FlyBase. DR GO; GO:0017077; F:oxidative phosphorylation uncoupler activity; IDA:UniProtKB. DR GO; GO:0015078; F:proton transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:1990845; P:adaptive thermogenesis; IBA:GO_Central. DR GO; GO:0032870; P:cellular response to hormone stimulus; IEA:Ensembl. DR GO; GO:1901373; P:lipid hydroperoxide transport; IEA:Ensembl. DR GO; GO:0006629; P:lipid metabolic process; TAS:ProtInc. DR GO; GO:1990542; P:mitochondrial transmembrane transport; IBA:GO_Central. DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; IBA:GO_Central. DR GO; GO:1902600; P:proton transmembrane transport; IDA:UniProtKB. DR GO; GO:0007585; P:respiratory gaseous exchange by respiratory system; TAS:ProtInc. DR GO; GO:0014823; P:response to activity; IEA:Ensembl. DR GO; GO:0009409; P:response to cold; IBA:GO_Central. DR GO; GO:1901557; P:response to fenofibrate; IEA:Ensembl. DR GO; GO:0051384; P:response to glucocorticoid; IEA:Ensembl. DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl. DR GO; GO:0032868; P:response to insulin; IEA:Ensembl. DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl. DR GO; GO:0000303; P:response to superoxide; IEA:Ensembl. DR FunFam; 1.50.40.10:FF:000008; Mitochondrial uncoupling protein 2; 1. DR Gene3D; 1.50.40.10; Mitochondrial carrier domain; 1. DR InterPro; IPR002067; MCP. DR InterPro; IPR023395; MCP_dom_sf. DR InterPro; IPR018108; MCP_transmembrane. DR InterPro; IPR050391; Mito_Metabolite_Transporter. DR PANTHER; PTHR45618; MITOCHONDRIAL DICARBOXYLATE CARRIER-RELATED; 1. DR Pfam; PF00153; Mito_carr; 3. DR PRINTS; PR00784; MTUNCOUPLING. DR SUPFAM; SSF103506; Mitochondrial carrier; 1. DR PROSITE; PS50920; SOLCAR; 3. PE 1: Evidence at protein level; KW Alternative splicing; Diabetes mellitus; Disease variant; Membrane; KW Mitochondrion; Mitochondrion inner membrane; Obesity; KW Proteomics identification; Reference proteome; Repeat; Transmembrane; KW Transmembrane helix; Transport. FT CHAIN 1..312 FT /note="Putative mitochondrial transporter UCP3" FT /id="PRO_0000090672" FT TOPO_DOM 1..10 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000250|UniProtKB:P56501" FT TRANSMEM 11..32 FT /note="Helical; Name=1" FT /evidence="ECO:0000255" FT TOPO_DOM 33..76 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000250|UniProtKB:P56501" FT TRANSMEM 77..99 FT /note="Helical; Name=2" FT /evidence="ECO:0000255" FT TOPO_DOM 100..119 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000250|UniProtKB:P56501" FT TRANSMEM 120..136 FT /note="Helical; Name=3" FT /evidence="ECO:0000255" FT TOPO_DOM 137..183 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000250|UniProtKB:P56501" FT TRANSMEM 184..200 FT /note="Helical; Name=4" FT /evidence="ECO:0000255" FT TOPO_DOM 201..217 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000250|UniProtKB:P56501" FT TRANSMEM 218..237 FT /note="Helical; Name=5" FT /evidence="ECO:0000255" FT TOPO_DOM 238..271 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000250|UniProtKB:P56501" FT TRANSMEM 272..294 FT /note="Helical; Name=6" FT /evidence="ECO:0000255" FT TOPO_DOM 295..312 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000250|UniProtKB:P56501" FT REPEAT 11..105 FT /note="Solcar 1" FT REPEAT 114..206 FT /note="Solcar 2" FT REPEAT 215..300 FT /note="Solcar 3" FT REGION 279..301 FT /note="Purine nucleotide binding" FT /evidence="ECO:0000250" FT VAR_SEQ 114..216 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_003270" FT VAR_SEQ 276..312 FT /note="Missing (in isoform UCP3S)" FT /evidence="ECO:0000305" FT /id="VSP_003271" FT VARIANT 9 FT /note="V -> M (in dbSNP:rs8179180)" FT /id="VAR_050136" FT VARIANT 70 FT /note="R -> W (in severe obesity with type 2 diabetes; FT dbSNP:rs17848368)" FT /evidence="ECO:0000269|Ref.16" FT /id="VAR_004407" FT VARIANT 102 FT /note="V -> I (in obesity; dbSNP:rs2229707)" FT /evidence="ECO:0000269|PubMed:9769326" FT /id="VAR_004408" FT CONFLICT 193..194 FT /note="NC -> KS (in Ref. 5; AAC18822)" FT /evidence="ECO:0000305" SQ SEQUENCE 312 AA; 34216 MW; D0E04A8DB352B17C CRC64; MVGLKPSDVP PTMAVKFLGA GTAACFADLV TFPLDTAKVR LQIQGENQAV QTARLVQYRG VLGTILTMVR TEGPCSPYNG LVAGLQRQMS FASIRIGLYD SVKQVYTPKG ADNSSLTTRI LAGCTTGAMA VTCAQPTDVV KVRFQASIHL GPSRSDRKYS GTMDAYRTIA REEGVRGLWK GTLPNIMRNA IVNCAEVVTY DILKEKLLDY HLLTDNFPCH FVSAFGAGFC ATVVASPVDV VKTRYMNSPP GQYFSPLDCM IKMVAQEGPT AFYKGFTPSF LRLGSWNVVM FVTYEQLKRA LMKVQMLRES PF //