ID UCP2_RAT Reviewed; 309 AA.
AC P56500; O70178; O88183; Q6GST1;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 15-JUL-1998, sequence version 1.
DT 27-MAR-2024, entry version 147.
DE RecName: Full=Dicarboxylate carrier SLC25A8 {ECO:0000250|UniProtKB:P55851};
DE AltName: Full=Mitochondrial uncoupling protein 2;
DE Short=UCP 2;
DE AltName: Full=Solute carrier family 25 member 8;
GN Name=Ucp2; Synonyms=Slc25a8;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=White adipose tissue;
RA Strobel A., Strosberg A.D., Issad T.;
RL Submitted (DEC-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Brown adipose tissue;
RX PubMed=9414126; DOI=10.1016/s0014-5793(97)01381-1;
RA Matsuda J., Hosoda K., Itoh H., Son C., Doi K., Tanaka T., Fukunaga Y.,
RA Inoue G., Nishimura H., Yoshimasa Y., Yamori Y., Nakao K.;
RT "Cloning of rat uncoupling protein-3 and uncoupling protein-2 cDNAs: their
RT gene expression in rats fed high-fat diet.";
RL FEBS Lett. 418:200-204(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Spleen;
RA Yamazaki K., Yoshitomi H., Tanaka I.;
RL Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Wistar; TISSUE=Brain;
RX PubMed=9512646; DOI=10.1016/s0005-2760(97)00188-4;
RA Hidaka S., Kakuma T., Yoshimatsu H., Yasunaga S., Kurokawa M., Sakata T.;
RT "Molecular cloning of rat uncoupling protein 2 cDNA and its expression in
RT genetically obese Zucker fatty (fa/fa) rats.";
RL Biochim. Biophys. Acta 1389:178-186(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pituitary;
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).
CC -!- FUNCTION: Antiporter that exports dicarboxylate intermediates of the
CC Krebs cycle in exchange for phosphate plus a proton across the inner
CC membrane of mitochondria, a process driven by mitochondrial motive
CC force with an overall impact on glycolysis, glutaminolysis and
CC glutathione-dependent redox balance. Continuous export of oxaloacetate
CC and related four-carbon dicarboxylates from mitochondrial matrix into
CC the cytosol negatively regulates the oxidation of acetyl-CoA substrates
CC via the Krebs cycle lowering the ATP/ADP ratio and reactive oxygen
CC species (ROS) production (By similarity). May mediate inducible proton
CC entry into the mitochondrial matrix affecting ATP turnover as a
CC protection mechanism against oxidative stress. The proton currents are
CC most likely associated with fatty acid flipping across the inner
CC membrane of mitochondria in a metabolic process regulated by free fatty
CC acids and purine nucleotides (By similarity). Regulates the use of
CC glucose as a source of energy. Required for glucose-induced DRP1-
CC dependent mitochondrial fission and neuron activation in the
CC ventromedial nucleus of the hypothalamus (VMH). This mitochondrial
CC adaptation mechanism modulates the VMH pool of glucose-excited neurons
CC with an impact on systemic glucose homeostasis. Regulates ROS levels
CC and metabolic reprogramming of macrophages during the resolution phase
CC of inflammation. Attenuates ROS production in response to IL33 to
CC preserve the integrity of the Krebs cycle required for persistent
CC production of itaconate and subsequent GATA3-dependent differentiation
CC of inflammation-resolving alternatively activated macrophages (By
CC similarity). Can unidirectionally transport anions including L-malate,
CC L-aspartate, phosphate and chloride ions (By similarity). Does not
CC mediate adaptive thermogenesis (By similarity).
CC {ECO:0000250|UniProtKB:P55851, ECO:0000250|UniProtKB:P70406}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(in) + L-aspartate(out) + phosphate(in) = H(+)(out) + L-
CC aspartate(in) + phosphate(out); Xref=Rhea:RHEA:73307,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29991, ChEBI:CHEBI:43474;
CC Evidence={ECO:0000250|UniProtKB:P55851};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(in) + oxaloacetate(out) + phosphate(in) = H(+)(out) +
CC oxaloacetate(in) + phosphate(out); Xref=Rhea:RHEA:73303,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16452, ChEBI:CHEBI:43474;
CC Evidence={ECO:0000250|UniProtKB:P55851};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(S)-malate(out) + H(+)(in) + phosphate(in) = (S)-malate(in) +
CC H(+)(out) + phosphate(out); Xref=Rhea:RHEA:73299, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15589, ChEBI:CHEBI:43474;
CC Evidence={ECO:0000250|UniProtKB:P55851};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(in) + malonate(out) + phosphate(in) = H(+)(out) +
CC malonate(in) + phosphate(out); Xref=Rhea:RHEA:73387,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15792, ChEBI:CHEBI:43474;
CC Evidence={ECO:0000250|UniProtKB:P55851};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(in) + phosphate(in) + sulfate(out) = H(+)(out) +
CC phosphate(out) + sulfate(in); Xref=Rhea:RHEA:73391,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16189, ChEBI:CHEBI:43474;
CC Evidence={ECO:0000250|UniProtKB:P55851};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(S)-malate(out) = (S)-malate(in); Xref=Rhea:RHEA:74555,
CC ChEBI:CHEBI:15589; Evidence={ECO:0000250|UniProtKB:P55851};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-aspartate(out) = L-aspartate(in); Xref=Rhea:RHEA:66332,
CC ChEBI:CHEBI:29991; Evidence={ECO:0000250|UniProtKB:P55851};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=phosphate(in) = phosphate(out); Xref=Rhea:RHEA:32823,
CC ChEBI:CHEBI:43474; Evidence={ECO:0000250|UniProtKB:P55851};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=chloride(in) = chloride(out); Xref=Rhea:RHEA:29823,
CC ChEBI:CHEBI:17996; Evidence={ECO:0000250|UniProtKB:P55851};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(in) = H(+)(out); Xref=Rhea:RHEA:34979, ChEBI:CHEBI:15378;
CC Evidence={ECO:0000250|UniProtKB:P55851,
CC ECO:0000250|UniProtKB:P70406};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a long-chain fatty acid(out) = a long-chain fatty acid(in);
CC Xref=Rhea:RHEA:39283, ChEBI:CHEBI:57560;
CC Evidence={ECO:0000250|UniProtKB:P70406};
CC -!- SUBUNIT: Homotetramer. Adopts an asymmetrical dimer of dimers
CC functional form. {ECO:0000250|UniProtKB:P55851}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000250|UniProtKB:P70406}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Expressed in a variety of organs, with predominant
CC expression in the heart, lung and spleen.
CC -!- DOMAIN: The GDP-binding domain is located within the hydrophilic
CC cavity, with GDP phosphates likely forming salt bridges with the
CC charged residues, Lys-141 and Arg-185. {ECO:0000250|UniProtKB:P70406}.
CC -!- DOMAIN: The long-chain fatty acid-binding domain consists of an
CC hydrophobic groove between peripheral transmembrane helices 1 and 6
CC near the matrix side. {ECO:0000250|UniProtKB:P70406}.
CC -!- SIMILARITY: Belongs to the mitochondrial carrier (TC 2.A.29) family.
CC {ECO:0000305}.
CC -!- CAUTION: The role of UCP2/SLC25A8 in mitochondrial proton conductance
CC is a matter of debate. It was initially suggested that it mediates
CC proton leak that increases net proton conductance in response to ROS
CC such as reactive alkenals generated during fatty acid oxidation in
CC mitochondria. By lowering the proton motive force, it would provide for
CC feedback control of mitochondrial ROS metabolism limiting extensive ROS
CC production and protecting cells against oxidative stress. This activity
CC and its potential regulation by ubiquinones and nucleotides was
CC disputed by later studies, which failed to reproduce the effect on
CC proton conductance under physiological conditions. Rather than
CC 'uncoupling' the link between electron transfer and ATP synthesis, it
CC may couple metabolite transport to proton flux to allow for optimal ATP
CC turnover. {ECO:0000250|UniProtKB:P55851, ECO:0000250|UniProtKB:P70406}.
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DR EMBL; AF039033; AAC98733.1; -; mRNA.
DR EMBL; AB006613; BAA23383.1; -; mRNA.
DR EMBL; AB010743; BAA25698.1; -; mRNA.
DR EMBL; AB005143; BAA28832.1; -; mRNA.
DR EMBL; BC062230; AAH62230.1; -; mRNA.
DR RefSeq; NP_062227.2; NM_019354.3.
DR AlphaFoldDB; P56500; -.
DR BMRB; P56500; -.
DR STRING; 10116.ENSRNOP00000024156; -.
DR PhosphoSitePlus; P56500; -.
DR PaxDb; 10116-ENSRNOP00000024156; -.
DR Ensembl; ENSRNOT00000024156.6; ENSRNOP00000024156.2; ENSRNOG00000017854.6.
DR Ensembl; ENSRNOT00065041580; ENSRNOP00065033972; ENSRNOG00065024250.
DR GeneID; 54315; -.
DR KEGG; rno:54315; -.
DR UCSC; RGD:3932; rat.
DR AGR; RGD:3932; -.
DR CTD; 7351; -.
DR RGD; 3932; Ucp2.
DR eggNOG; KOG0753; Eukaryota.
DR GeneTree; ENSGT00940000159524; -.
DR HOGENOM; CLU_015166_14_2_1; -.
DR InParanoid; P56500; -.
DR OMA; CSTIDAY; -.
DR OrthoDB; 1832865at2759; -.
DR PhylomeDB; P56500; -.
DR TreeFam; TF323211; -.
DR Reactome; R-RNO-167826; The fatty acid cycling model.
DR Reactome; R-RNO-167827; The proton buffering model.
DR PRO; PR:P56500; -.
DR Proteomes; UP000002494; Chromosome 1.
DR Bgee; ENSRNOG00000017854; Expressed in spleen and 19 other cell types or tissues.
DR Genevisible; P56500; RN.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031966; C:mitochondrial membrane; ISO:RGD.
DR GO; GO:0015297; F:antiporter activity; ISS:UniProtKB.
DR GO; GO:0015108; F:chloride transmembrane transporter activity; ISO:RGD.
DR GO; GO:0015183; F:L-aspartate transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0015140; F:malate transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0015131; F:oxaloacetate transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0017077; F:oxidative phosphorylation uncoupler activity; IBA:GO_Central.
DR GO; GO:0140787; F:phosphate ion uniporter activity; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0015078; F:proton transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0008271; F:secondary active sulfate transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:1990845; P:adaptive thermogenesis; IBA:GO_Central.
DR GO; GO:0015740; P:C4-dicarboxylate transport; ISS:UniProtKB.
DR GO; GO:0034198; P:cellular response to amino acid starvation; IEP:RGD.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEP:RGD.
DR GO; GO:0032870; P:cellular response to hormone stimulus; IEP:RGD.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IEP:RGD.
DR GO; GO:0071284; P:cellular response to lead ion; IEP:RGD.
DR GO; GO:0006541; P:glutamine metabolic process; ISS:UniProtKB.
DR GO; GO:0006096; P:glycolytic process; ISS:UniProtKB.
DR GO; GO:0097421; P:liver regeneration; IEP:RGD.
DR GO; GO:0030225; P:macrophage differentiation; ISS:UniProtKB.
DR GO; GO:0000266; P:mitochondrial fission; ISS:UniProtKB.
DR GO; GO:1990542; P:mitochondrial transmembrane transport; ISS:UniProtKB.
DR GO; GO:0006839; P:mitochondrial transport; IDA:RGD.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:RGD.
DR GO; GO:0061179; P:negative regulation of insulin secretion involved in cellular response to glucose stimulus; IMP:RGD.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; ISO:RGD.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; ISS:UniProtKB.
DR GO; GO:0051881; P:regulation of mitochondrial membrane potential; ISO:RGD.
DR GO; GO:0009409; P:response to cold; IBA:GO_Central.
DR GO; GO:0071548; P:response to dexamethasone; IEP:RGD.
DR GO; GO:0070542; P:response to fatty acid; IEP:RGD.
DR GO; GO:0009749; P:response to glucose; IEP:RGD.
DR GO; GO:0001666; P:response to hypoxia; IEP:RGD.
DR GO; GO:0000303; P:response to superoxide; IDA:RGD.
DR Gene3D; 1.50.40.10; Mitochondrial carrier domain; 1.
DR InterPro; IPR002067; Mit_carrier.
DR InterPro; IPR018108; Mitochondrial_sb/sol_carrier.
DR InterPro; IPR023395; Mt_carrier_dom_sf.
DR PANTHER; PTHR45618; MITOCHONDRIAL DICARBOXYLATE CARRIER-RELATED; 1.
DR PANTHER; PTHR45618:SF1; MITOCHONDRIAL UNCOUPLING PROTEIN 2; 1.
DR Pfam; PF00153; Mito_carr; 3.
DR PRINTS; PR00784; MTUNCOUPLING.
DR SUPFAM; SSF103506; Mitochondrial carrier; 1.
DR PROSITE; PS50920; SOLCAR; 3.
PE 2: Evidence at transcript level;
KW Membrane; Mitochondrion; Mitochondrion inner membrane; Reference proteome;
KW Repeat; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..309
FT /note="Dicarboxylate carrier SLC25A8"
FT /id="PRO_0000090667"
FT TOPO_DOM 1..16
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000305"
FT TRANSMEM 17..40
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:P70406"
FT TOPO_DOM 41..77
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000305"
FT TRANSMEM 78..103
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:P70406"
FT TOPO_DOM 104..119
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000305"
FT TRANSMEM 120..145
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:P70406"
FT TOPO_DOM 146..173
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000305"
FT TRANSMEM 174..199
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:P70406"
FT TOPO_DOM 200..217
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000305"
FT TRANSMEM 218..242
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:P70406"
FT TOPO_DOM 243..268
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000305"
FT TRANSMEM 269..294
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:P70406"
FT TOPO_DOM 295..309
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000305"
FT REPEAT 11..106
FT /note="Solcar 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00282"
FT REPEAT 114..203
FT /note="Solcar 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00282"
FT REPEAT 212..297
FT /note="Solcar 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00282"
FT REGION 16..63
FT /note="Important for interaction with long-chain fatty
FT acids"
FT /evidence="ECO:0000250|UniProtKB:P70406"
FT REGION 278..285
FT /note="Important for interaction with long-chain fatty
FT acids"
FT /evidence="ECO:0000250|UniProtKB:P70406"
FT SITE 141
FT /note="Important for inhibition by GDP"
FT /evidence="ECO:0000250|UniProtKB:P70406"
FT SITE 185
FT /note="Important for inhibition by GDP"
FT /evidence="ECO:0000250|UniProtKB:P70406"
FT CONFLICT 9
FT /note="V -> L (in Ref. 4; BAA28832)"
FT /evidence="ECO:0000305"
FT CONFLICT 268
FT /note="A -> T (in Ref. 3; BAA25698 and 5; AAH62230)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 309 AA; 33377 MW; 3297935CF997AA0E CRC64;
MVGFKATDVP PTATVKFLGA GTAACIADLI TFPLDTAKVR LQIQGESQGL ARTAASAQYR
GVLGTILTMV RTEGPRSLYN GLVAGLQRQM SFASVRIGLY DSVKQFYTKG SEHAGIGSRL
LAGSTTGALA VAVAQPTDVV KVRFQAQARA GGGRRYQSTV EAYKTIAREE GIRGLWKGTS
PNVARNAIVN CTELVTYDLI KDTLLKANLM TDDLPCHFTS AFGAGFCTTV IASPVDVVKT
RYMNSALGQY HSAGHCALTM LRKEGPRAFY KGFMPSFLRL GSWNVVMFVT YEQLKRALMA
AYESREAPF
//
