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   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.
DR   Genevisible; P56500; RN.
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
//