UCP2

Summary

UCP2 (uncoupling protein 2, HGNC:12518) is a protein-coding gene on chromosome 11q13.4, encoding Dicarboxylate carrier SLC25A8 (P55851). Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria, a process driven by mitochondrial motive force with an overall impact on glycolysis, glutaminolysis and glutathione-dependent….

Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP). UCPs separate oxidative phosphorylation from ATP synthesis with energy dissipated as heat, also referred to as the mitochondrial proton leak. UCPs facilitate the transfer of anions from the inner to the outer mitochondrial membrane and the return transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells. Tissue specificity occurs for the different UCPs and the exact methods of how UCPs transfer H+/OH- are not known. UCPs contain the three homologous protein domains of MACPs. This gene is expressed in many tissues, with the greatest expression in skeletal muscle. It is thought to play a role in nonshivering thermogenesis, obesity and diabetes. Chromosomal order is 5’-UCP3-UCP2-3'.

Source: NCBI Gene 7351 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperinsulinism due to UCP2 deficiency (Moderate, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 118 total
• Phenotypes (HPO): 26
• MANE Select transcript: NM_003355

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12518
Approved symbol	UCP2
Name	uncoupling protein 2
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	SLC25A8
Ensembl gene	ENSG00000175567
Ensembl biotype	protein_coding
OMIM	601693
Entrez	7351

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 16 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000310473, ENST00000536983, ENST00000539330, ENST00000539764, ENST00000541027, ENST00000542615, ENST00000543714, ENST00000544615, ENST00000545212, ENST00000545562, ENST00000663595, ENST00000880147, ENST00000880148, ENST00000880149, ENST00000880150, ENST00000880151, ENST00000880152, ENST00000880153, ENST00000880154, ENST00000912379, ENST00000952750, ENST00000952751

RefSeq mRNA: 8 — MANE Select: NM_003355 NM_001381943, NM_001381944, NM_001381945, NM_001381947, NM_001381948, NM_001381949, NM_001381950, NM_003355

CCDS: CCDS8228

Canonical transcript exons

ENST00000663595 — 8 exons

Exon	Start	End
ENSE00001184349	73975491	73975671
ENSE00001184355	73976823	73977017
ENSE00001184362	73981476	73981632
ENSE00001184368	73974672	73975121
ENSE00001184370	73978253	73978477
ENSE00001252503	73977886	73978096
ENSE00003665375	73976641	73976742
ENSE00004283638	73982721	73982843

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 115.1936 / max 1682.8982, expressed in 1668 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121292	108.7468	1658
121294	1.4260	457
121287	1.3471	534
121293	1.3118	420
121289	0.9929	444
121286	0.6742	359
121288	0.4460	264
121295	0.2489	122

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.39	gold quality
bronchial epithelial cell	CL:0002328	99.36	gold quality
epithelium of bronchus	UBERON:0002031	99.26	gold quality
bronchus	UBERON:0002185	99.26	gold quality
right uterine tube	UBERON:0001302	99.21	gold quality
spleen	UBERON:0002106	98.96	gold quality
epithelium of nasopharynx	UBERON:0001951	98.86	gold quality
vermiform appendix	UBERON:0001154	98.84	gold quality
nasopharynx	UBERON:0001728	98.84	gold quality
blood	UBERON:0000178	98.83	gold quality
trabecular bone tissue	UBERON:0002483	98.82	gold quality
nasal cavity epithelium	UBERON:0005384	98.78	gold quality
palpebral conjunctiva	UBERON:0001812	98.66	gold quality
leukocyte	CL:0000738	98.65	gold quality
mononuclear cell	CL:0000842	98.59	gold quality
monocyte	CL:0000576	98.57	gold quality
lymph node	UBERON:0000029	98.25	gold quality
bone marrow cell	CL:0002092	98.10	gold quality
thymus	UBERON:0002370	97.90	gold quality
parotid gland	UBERON:0001831	97.65	gold quality
bone marrow	UBERON:0002371	97.65	gold quality
amniotic fluid	UBERON:0000173	97.42	gold quality
ileal mucosa	UBERON:0000331	97.18	gold quality
caecum	UBERON:0001153	97.04	gold quality
bone element	UBERON:0001474	97.01	gold quality
trachea	UBERON:0003126	96.83	gold quality
pylorus	UBERON:0001166	96.79	gold quality
nasal cavity mucosa	UBERON:0001826	96.62	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.57	gold quality
synovial joint	UBERON:0002217	96.36	gold quality

Single-cell (SCXA)

Detected in 28 experiment(s), a significant marker in 24.

Experiment	Marker?	Max mean expression
E-CURD-120	yes	2617.42
E-HCAD-13	yes	2278.36
E-HCAD-4	yes	53.75
E-MTAB-6701	yes	47.32
E-CURD-114	yes	44.58
E-HCAD-10	yes	42.84
E-HCAD-6	yes	35.34
E-MTAB-10287	yes	25.46
E-MTAB-8410	yes	24.61
E-HCAD-1	yes	21.35
E-CURD-122	yes	19.75
E-MTAB-9067	yes	17.38
E-MTAB-8498	yes	12.13
E-MTAB-5061	yes	12.01
E-GEOD-125970	yes	9.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXA1, HIF1A, HNF1A, IRF6, MYOD1, MYOG, PDX1, PPARA, PPARG, PPARGC1B, SMAD4, SP1, SREBF1, SREBF2, STAT3, USF1

miRNA regulators (miRDB)

31 targeting UCP2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-1246	98.54	66.21	959
HSA-MIR-3668	98.52	68.76	951
HSA-MIR-6873-5P	98.45	66.14	1417
HSA-MIR-4329	97.68	66.26	1003
HSA-MIR-6869-5P	97.17	67.06	634
HSA-MIR-6760-3P	96.35	68.31	1001
HSA-MIR-1538	85.86	60.08	75

Literature-anchored findings (GeneRIF, showing 40)

• Glucose induces and leptin decreases expression of uncoupling protein-2 mRNA in human islets. (PMID:11904148)
• microsatellite markers at the UCP2/UCP3 locus on chromosome 11q13 in anorexia nervosa (PMID:11920154)
• evidence for its function as a metabolic regulator (REVIEW) (PMID:11935148)
• hypothesis that recombinant human uncoupling protein-2 (UCP2) ectopically expressed in bacterial inclusion bodies binds nucleotides in a manner identical with the nucleotide-inhibited uncoupling that is observed in kidney mitochondria (PMID:12030845)
• Decreased mitochondrial proton leak and reduced expression in skeletal muscle of obese diet-resistant women (PMID:12145158)
• A functional polymorphism in the promoter enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans (PMID:12401727)
• purine nucleotides must be the physiological inhibitors of UCP2-mediated uncoupling in vivo. (PMID:12670931)
• there is a unique, near-uniform distribution of the uncoupling protein 2 insertion/deletion polymorphism in Tonga which may be relevant to the prevalence of obesity and type 2 diabetes (PMID:12690079)
• the common -866G/A polymorphism in the UCP2 gene may contribute to the biological variation of insulin secretion (PMID:12716765)
• UCPs in adipose tissue may play a role in the reduction in 24-h energy expenditure observed in post-obese individuals. (PMID:12720538)
• study of isolation, refolding, transport properties, and regulation of recombinant UCP2 (PMID:12734183)
• No evidence for involvement of the promoter polymorphism -866 G/A of the UCP2 gene in childhood-onset obesity in humans (PMID:12746756)
• the recent advancements on the role of UCP2 in the brain and portray this uncoupler as an important player in normal neuronal function as well as a key cell death-suppressing device. (PMID:12787871)
• These data are the first to suggest that polymorphisms in the UCP2 gene may be genetic risk factors of spina bifida. (PMID:12797456)
• Overexpression of human UCP2 attenuates reactive oxygen species generation and prevents mitochondrial Ca2+ overload in cultured neonatal rat cardiomyocytes revealing a novel mechanism of cardioprotection (PMID:12855674)
• Data suggest that uncoupling protein-2 is an inducible protein that is neuroprotective by activating cellular redox signaling or by inducing mild mitochondrial uncoupling that prevents the release of apoptogenic proteins. (PMID:12858170)
• Uncoupling protein-2 variants show significant effects on insulin secretion in interaction with family-specific factors. However, the associated allele and the effects on gene expression are opposite to those reported previously. (PMID:12915397)
• Mitochondrial UCPs precondition neurons by dissociating cellular energy production from that of free radicals to withstand the harmful effects of cellular stress occurring in a variety of neurodegenerative disorders, including epilepsy. (PMID:12960023)
• variation of the uncoupling protein 2 promoter is not associated with obesity or obesity-related intermediary phenotypes in Danish subjects (PMID:14627764)
• Uncoupling protein 2 has a role in neuroprotection [review] (PMID:14659466)
• Juvenile obese subjects who are homozygous for the A variant have an increased ratio (3.6 +/- 1.2) of calories derived from carbohydrates to those from lipids. (PMID:14693721)
• In type 2 diabetes there is a significant gene to gene interaction between the Ala55Val polymorphism in the uncoupling protein 2 gene ( UCP2) and the 161C>T polymorphism in the exon 6 of ppargamma. (PMID:14730379)
• UCP2 promoter polymorphism -866G/A does not affect obesity in Japanese type 2 diabetic patients but affects its transcription in beta-cells. (PMID:14747301)
• UCP2 allelic variants may not have a direct role in the pathogenesis and development of obesity. (PMID:14759071)
• Mitochondrial UCP2 in circulating monocytes may prevent excessive accumulation of monocytes/macrophages in the arterial wall, thereby reducing atherosclerotic plaque formation. (PMID:15016641)
• Polymorphism of uncoupling protein 2 gene is associated with hypertension, and suggests the possibility of uncoupling protein 2 gene as a target molecule for studies on the etiology and treatment of hypertension. (PMID:15106800)
• No association between the different polymorphisms and diabetic nephropathy. (PMID:15120704)
• The -866A/A genotype was associated with diabetes in women, but not in men. The -866A/A genotype of the UCP2 gene may contribute to diabetes susceptibility by affecting insulin sensitivity. (PMID:15220218)
• UCP2 may be part of a novel adaptive response by which oxidative stress is modulated in colon cancer (PMID:15448008)
• UCP2 has a role in hydroperoxy fatty acid cycling (PMID:15475368)
• anion channel structure of UCP2 protein is oligomeric and the second transmembrane domain is essential for the voltage-dependence of this anion channel (PMID:15527803)
• Single nucleotid polymorphism is associated with type 2 diabetes risk in Italy. (PMID:15562023)
• The hypothesis that differences in the UCP-2 genes influence the susceptibility to anorexia nervossa was not supported. (PMID:15564896)
• Our results suggest a role of UCP2 in atherogenesis (PMID:15604415)
• The present results expose the critical importance of UCP2 in normal nigral dopamine cell metabolism. (PMID:15634780)
• UCP-2 can modify atherosclerotic processes inhuman vascular muscle smooth cells in response to high glucose and Angiotensin II. (PMID:15827742)
• reduction of free fatty acids(FFAs) induced by bilio-pancreatic diversion acts in inhibiting FFA transportation to the mitochondria uncoupling protein 2 (UCP-2), contributing to the decreased lipid oxidation inside the adipose tissue (PMID:15833942)
• UCP2 functions as a physiologic regulator of ROS generation in endothelial cells. (PMID:15905464)
• Our results suggest that the LEP and UCP2/UCP3 genes are unlikely to have a substantial effect on variation in obesity phenotypes in this particular US Caucasian population. (PMID:15910756)
• UCP2 promoter polymorphism may contribute to multiple sclerosis susceptibility by regulating the level of UCP2 protein in the central nervous and/or the immune systems. (PMID:16021520)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ucp2	ENSDARG00000043154
mus_musculus	Ucp2	ENSMUSG00000033685
rattus_norvegicus	Ucp2	ENSRNOG00000017854

Paralogs (49): SLC25A13 (ENSG00000004864), SLC25A5 (ENSG00000005022), SLC25A39 (ENSG00000013306), SLC25A40 (ENSG00000075303), SLC25A3 (ENSG00000075415), SLC25A43 (ENSG00000077713), SLC25A24 (ENSG00000085491), SLC25A1 (ENSG00000100075), SLC25A17 (ENSG00000100372), SLC25A14 (ENSG00000102078), SLC25A15 (ENSG00000102743), SLC25A11 (ENSG00000108528), UCP1 (ENSG00000109424), SLC25A36 (ENSG00000114120), SLC25A12 (ENSG00000115840), SLC25A2 (ENSG00000120329), SLC25A51 (ENSG00000122696), SLC25A16 (ENSG00000122912), SLC25A35 (ENSG00000125434), SLC25A19 (ENSG00000125454), SLC25A23 (ENSG00000125648), SLC25A47 (ENSG00000140107), SLC25A52 (ENSG00000141437), SLC25A38 (ENSG00000144659), SLC25A26 (ENSG00000144741), SLC25A48 (ENSG00000145832), SLC25A37 (ENSG00000147454), SLC25A25 (ENSG00000148339), SLC25A31 (ENSG00000151475), SLC25A4 (ENSG00000151729), SLC25A27 (ENSG00000153291), SLC25A28 (ENSG00000155287), SLC25A44 (ENSG00000160785), SLC25A45 (ENSG00000162241), SLC25A34 (ENSG00000162461), SLC25A32 (ENSG00000164933), SLC25A6 (ENSG00000169100), SLC25A33 (ENSG00000171612), SLC25A30 (ENSG00000174032), UCP3 (ENSG00000175564)

Protein

Protein identifiers

Dicarboxylate carrier SLC25A8 — P55851 (reviewed: P55851)

Alternative names: Mitochondrial uncoupling protein 2, Solute carrier family 25 member 8, UCPH

All UniProt accessions (4): P55851, F5GX45, F5H312, H0YFQ0

UniProt curated annotations — full annotation on UniProt →

Function. Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria, a process driven by mitochondrial motive force with an overall impact on glycolysis, glutaminolysis and glutathione-dependent redox balance. Continuous export of oxaloacetate and related four-carbon dicarboxylates from mitochondrial matrix into the cytosol negatively regulates the oxidation of acetyl-CoA substrates via the Krebs cycle, lowering the ATP/ADP ratio and reactive oxygen species (ROS) production. May mediate inducible proton entry into the mitochondrial matrix affecting ATP turnover as a protection mechanism against oxidative stress. The proton currents are most likely associated with fatty acid flipping across the inner membrane of mitochondria in a metabolic process regulated by free fatty acids and purine nucleotides. Regulates the use of glucose as a source of energy. Required for glucose-induced DRP1-dependent mitochondrial fission and neuron activation in the ventromedial nucleus of the hypothalamus (VMH). This mitochondrial adaptation mechanism modulates the VMH pool of glucose-excited neurons with an impact on systemic glucose homeostasis. Regulates ROS levels and metabolic reprogramming of macrophages during the resolution phase of inflammation. Attenuates ROS production in response to IL33 to preserve the integrity of the Krebs cycle required for persistent production of itaconate and subsequent GATA3-dependent differentiation of inflammation-resolving alternatively activated macrophages. Can unidirectionally transport anions including L-malate, L-aspartate, phosphate and chloride ions. Does not mediate adaptive thermogenesis.

Subunit / interactions. Homotetramer. Adopts an asymmetrical dimer of dimers functional form.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Widely expressed in adult human tissues, including tissues rich in macrophages. Most expressed in white adipose tissue and skeletal muscle.

Activity regulation. Inhibited by pyridoxal- 5’-phosphate, bathophenanthroline, tannic acid, bromocresol purple, butylmalonate and phenylsuccinate. Proton conductance is activated by cardiolipin and long-chain free fatty acids and inhibited by purine nucleotides ATP and ADP. Chloride ion transporter activity is inhibited by long-chain free fatty acids.

Domain organisation. The GDP-binding domain is located within the hydrophilic cavity, with GDP phosphates likely forming salt bridges with the charged residues, Lys-141 and Arg-185. The long-chain fatty acid-binding domain consists of an hydrophobic groove between peripheral transmembrane helices 1 and 6 near the matrix side.

Polymorphism. Genetic variations in UCP2 define the body mass index quantitative trait locus 4 (BMIQ4) [MIM:607447]. A common polymorphism in the promoter of UCP2 has been shown to be associated with a decreased risk of obesity in middle-aged individuals.

Similarity. Belongs to the mitochondrial carrier (TC 2.A.29) family.

RefSeq proteins (8): NP_001368872, NP_001368873, NP_001368874, NP_001368876, NP_001368877, NP_001368878, NP_001368879, NP_003346* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002067	MCP	Family
IPR018108	MCP_transmembrane	Repeat
IPR023395	MCP_dom_sf	Homologous_superfamily
IPR050391	Mito_Metabolite_Transporter	Family

Pfam: PF00153

Catalyzed reactions (Rhea), 11 shown:

• chloride(in) = chloride(out) (RHEA:29823)
• phosphate(in) = phosphate(out) (RHEA:32823)
• H(+)(in) = H(+)(out) (RHEA:34979)
• a long-chain fatty acid(out) = a long-chain fatty acid(in) (RHEA:39283)
• L-aspartate(out) = L-aspartate(in) (RHEA:66332)
• (S)-malate(out) + phosphate(in) + H(+)(in) = (S)-malate(in) + phosphate(out) + H(+)(out) (RHEA:73299)
• oxaloacetate(out) + phosphate(in) + H(+)(in) = oxaloacetate(in) + phosphate(out) + H(+)(out) (RHEA:73303)
• L-aspartate(out) + phosphate(in) + H(+)(in) = L-aspartate(in) + phosphate(out) + H(+)(out) (RHEA:73307)
• malonate(out) + phosphate(in) + H(+)(in) = malonate(in) + phosphate(out) + H(+)(out) (RHEA:73387)
• sulfate(out) + phosphate(in) + H(+)(in) = sulfate(in) + phosphate(out) + H(+)(out) (RHEA:73391)
• (S)-malate(out) = (S)-malate(in) (RHEA:74555)

UniProt features (27 total): topological domain 7, transmembrane region 6, sequence variant 5, repeat 3, region of interest 2, site 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55851-F1	62.63	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 141 (important for inhibition by gdp); 185 (important for inhibition by gdp)

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-167826	The fatty acid cycling model

MSigDB gene sets: 543 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, MCLACHLAN_DENTAL_CARIES_UP, GOBP_RESPONSE_TO_COLD, PID_HNF3B_PATHWAY, MODULE_151, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS

GO Biological Process (36): mitochondrial fission (GO:0000266), response to superoxide (GO:0000303), response to hypoxia (GO:0001666), glycolytic process (GO:0006096), L-glutamine metabolic process (GO:0006541), response to cold (GO:0009409), C4-dicarboxylate transport (GO:0015740), long-chain fatty acid transport (GO:0015909), macrophage differentiation (GO:0030225), cellular response to insulin stimulus (GO:0032869), cellular response to amino acid starvation (GO:0034198), negative regulation of neuron apoptotic process (GO:0043524), regulation of mitochondrial membrane potential (GO:0051881), negative regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0061179), response to fatty acid (GO:0070542), cellular response to lead ion (GO:0071284), cellular response to glucose stimulus (GO:0071333), response to dexamethasone (GO:0071548), reactive oxygen species metabolic process (GO:0072593), liver regeneration (GO:0097421), negative regulation of calcium import into the mitochondrion (GO:0110099), positive regulation of cold-induced thermogenesis (GO:0120162), proton transmembrane transport (GO:1902600), mitochondrial transmembrane transport (GO:1990542), adaptive thermogenesis (GO:1990845), mitochondrial transport (GO:0006839), response to glucose (GO:0009749), inorganic anion transport (GO:0015698), cellular response to hormone stimulus (GO:0032870), negative regulation of apoptotic process (GO:0043066), transmembrane transport (GO:0055085), L-aspartate transmembrane transport (GO:0070778), malate transmembrane transport (GO:0071423), oxaloacetate(2-) transmembrane transport (GO:1902356), sulfate transmembrane transport (GO:1902358), chloride transmembrane transport (GO:1902476)

GO Molecular Function (12): secondary active sulfate transmembrane transporter activity (GO:0008271), proton transmembrane transporter activity (GO:0015078), chloride transmembrane transporter activity (GO:0015108), oxaloacetate transmembrane transporter activity (GO:0015131), malate transmembrane transporter activity (GO:0015140), L-aspartate transmembrane transporter activity (GO:0015183), antiporter activity (GO:0015297), oxidative phosphorylation uncoupler activity (GO:0017077), GDP binding (GO:0019003), protein homodimerization activity (GO:0042803), phosphate ion uniporter activity (GO:0140787), protein binding (GO:0005515)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Mitochondrial Uncoupling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
C4-dicarboxylate transmembrane transporter activity	3
response to stress	2
secondary active transmembrane transporter activity	2
proton transmembrane transport	2
mitochondrion organization	1
organelle fission	1
response to oxygen radical	1
response to decreased oxygen levels	1
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase [NAD(P)+] (phosphorylating) activity	1
ADP catabolic process	1
ATP metabolic process	1
nicotinamide nucleotide metabolic process	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
response to temperature stimulus	1
dicarboxylic acid transport	1
fatty acid transport	1
myeloid leukocyte differentiation	1
mononuclear cell differentiation	1
response to insulin	1
cellular response to peptide hormone stimulus	1
cellular response to starvation	1
response to amino acid starvation	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
regulation of membrane potential	1
insulin secretion involved in cellular response to glucose stimulus	1
negative regulation of insulin secretion	1
negative regulation of response to stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1

Protein interactions and networks

STRING

2096 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UCP2	PPARGC1A	Q9UBK2	927
UCP2	LEP	P41159	885
UCP2	PPARG	P37231	847
UCP2	SREBF1	P36956	846
UCP2	GHRL	Q9UBU3	816
UCP2	INS	P01308	815
UCP2	PPARA	Q07869	808
UCP2	AGRP	O00253	778
UCP2	MICU1	Q9BPX6	778
UCP2	ADIPOQ	Q15848	776
UCP2	ACOX1	Q15067	774
UCP2	NPY	P01303	764
UCP2	ADRB3	P13945	748
UCP2	CPT1A	P50416	746
UCP2	PPARD	Q03181	741

IntAct

13 interactions, top by confidence:

A	B	Type	Score
KRTAP10-7	UCP2	psi-mi:“MI:0915”(physical association)	0.560
UCP2		psi-mi:“MI:0915”(physical association)	0.560
	UCP2	psi-mi:“MI:0915”(physical association)	0.560
UCP2	CST4	psi-mi:“MI:0914”(association)	0.530
UCP2	BTBD1	psi-mi:“MI:0915”(physical association)	0.400
UCP3	UCP2	psi-mi:“MI:0915”(physical association)	0.400
S100A6	VWA8	psi-mi:“MI:0914”(association)	0.350
pepP	UCP2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (45): KRTAP10-7 (Two-hybrid), KRTAP10-3 (Two-hybrid), ANXA1 (Affinity Capture-MS), AMY1C (Affinity Capture-MS), ZG16B (Affinity Capture-MS), CST4 (Affinity Capture-MS), CST2 (Affinity Capture-MS), FLG (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), ALDH3A1 (Affinity Capture-MS), MUC7 (Affinity Capture-MS), HAL (Affinity Capture-MS), PIGR (Affinity Capture-MS), IGHA2 (Affinity Capture-MS), CRNN (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K5L2, A0JN87, G3XP90, G3YAF3, O04619, O77792, O95847, O97562, P55851, P55916, P56499, P56500, P56501, P70406, Q08DK4, Q1LZB3, Q29RM1, Q2YDD9, Q3SZI5, Q3TZX3, Q3V132, Q4V9P0, Q505J6, Q5IS35, Q5NVC1, Q5R5A8, Q5RD81, Q5RFB7, Q5ZKP7, Q6DG32, Q6P036, Q6PGY3, Q7K566, Q8BZ09, Q922G0, Q96CQ1, Q99JD3, Q9BQT8, Q9BSK2, Q9C5M0

Diamond homologs: A0A0U2IR85, A0A3G9HRV8, A2CEQ0, A6RAY2, A6SL61, A7ER02, B0DK57, B8ZHC9, F1R4U0, G3YC86, G3YD89, G3YFS7, O13844, O94502, P32089, P33303, P34519, P38152, P53007, P55851, P56500, P70406, P79110, Q07534, Q10442, Q287T7, Q2UCW8, Q3SZI5, Q3ZBJ8, Q59KC4, Q5AVW1, Q5R5A8, Q66H23, Q68F18, Q6BH02, Q6C107, Q6C6I3, Q6GLJ0, Q6PGY3, Q7XA87

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

118 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	85
Likely benign	14
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1548 predictions. Top by Δscore:

Variant	Effect	Δscore
11:73975117:TGAAC:T	acceptor_gain	1.0000
11:73975119:AACCT:A	acceptor_loss	1.0000
11:73975120:ACC:A	acceptor_loss	1.0000
11:73975121:CCTAG:C	acceptor_loss	1.0000
11:73975122:C:CC	acceptor_gain	1.0000
11:73975122:CTAG:C	acceptor_loss	1.0000
11:73975489:AC:A	donor_gain	1.0000
11:73975490:CC:C	donor_gain	1.0000
11:73976636:CTCA:C	donor_loss	1.0000
11:73976639:A:AC	donor_gain	1.0000
11:73976639:AC:A	donor_gain	1.0000
11:73976639:ACCTG:A	donor_loss	1.0000
11:73976640:C:CG	donor_gain	1.0000
11:73976640:CC:C	donor_gain	1.0000
11:73976640:CCT:C	donor_gain	1.0000
11:73976640:CCTG:C	donor_gain	1.0000
11:73976640:CCTGT:C	donor_gain	1.0000
11:73976738:GGTCC:G	acceptor_gain	1.0000
11:73976739:GTCC:G	acceptor_gain	1.0000
11:73976740:TCC:T	acceptor_gain	1.0000
11:73976740:TCCC:T	acceptor_loss	1.0000
11:73976741:CC:C	acceptor_gain	1.0000
11:73976741:CCCTG:C	acceptor_gain	1.0000
11:73976742:CC:C	acceptor_gain	1.0000
11:73976743:C:CA	acceptor_loss	1.0000
11:73976743:C:CC	acceptor_gain	1.0000
11:73976744:T:A	acceptor_loss	1.0000
11:73976745:G:C	acceptor_gain	1.0000
11:73976745:G:GC	acceptor_gain	1.0000
11:73976819:ACAC:A	donor_loss	1.0000

AlphaMissense

1992 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:73977981:C:T	G81E	1.000
11:73975491:C:T	G272E	0.999
11:73975492:C:G	G272R	0.999
11:73975492:C:T	G272R	0.999
11:73975589:C:A	K239N	0.999
11:73975589:C:G	K239N	0.999
11:73975600:C:G	D236H	0.999
11:73976672:C:A	K201N	0.999
11:73976672:C:G	K201N	0.999
11:73976721:C:G	R185P	0.999
11:73976823:C:G	G178R	0.999
11:73976823:C:T	G178R	0.999
11:73976943:C:G	D138H	0.999
11:73976966:G:T	A130D	0.999
11:73977947:A:C	F92L	0.999
11:73977947:A:T	F92L	0.999
11:73977949:A:G	F92L	0.999
11:73977961:G:T	R88S	0.999
11:73977981:C:A	G81V	0.999
11:73977982:C:A	G81W	0.999
11:73977982:C:G	G81R	0.999
11:73977982:C:T	G81R	0.999
11:73978265:T:A	K38N	0.999
11:73978265:T:G	K38N	0.999
11:73978269:G:T	A37D	0.999
11:73978275:T:A	D35V	0.999
11:73978276:C:G	D35H	0.999
11:73975090:A:G	W283R	0.998
11:73975090:A:T	W283R	0.998
11:73975492:C:A	G272W	0.998

dbSNP variants (sampled 300 via entrez): RS1000251419 (11:73975931 G>A), RS1000379625 (11:73981655 A>C,G), RS1000527107 (11:73974349 A>G), RS1000601942 (11:73975580 G>A,T), RS1000611566 (11:73984159 G>C,T), RS1000671612 (11:73978547 C>G,T), RS1000705980 (11:73978801 C>T), RS1000712049 (11:73980409 A>C), RS1001671001 (11:73984740 G>T), RS1001675562 (11:73977287 C>G,T), RS1001706488 (11:73977533 G>A,C,T), RS1001729652 (11:73983056 C>A,T), RS1002409548 (11:73985199 T>G), RS1002517859 (11:73977810 T>C), RS1002701938 (11:73982290 G>C)

Disease associations

OMIM: gene MIM:601693 | disease phenotypes: MIM:125851

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperinsulinism due to UCP2 deficiency	Moderate	Autosomal dominant

Mondo (2): maturity-onset diabetes of the young type 2 (MONDO:0007453), hyperinsulinism due to UCP2 deficiency (MONDO:0017183)

Orphanet (1): MODY (Orphanet:552)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000713	Agitation
HP:0000825	Hyperinsulinemic hypoglycemia
HP:0000980	Pallor
HP:0001069	Episodic hyperhidrosis
HP:0001254	Lethargy
HP:0001279	Syncope
HP:0001325	Hypoglycemic coma
HP:0001520	Large for gestational age
HP:0001639	Hypertrophic cardiomyopathy
HP:0001649	Tachycardia
HP:0001962	Palpitations
HP:0001985	Hypoketotic hypoglycemia
HP:0001988	Recurrent hypoglycemia
HP:0002133	Status epilepticus
HP:0002173	Hypoglycemic seizures
HP:0002240	Hepatomegaly
HP:0002329	Drowsiness
HP:0002591	Polyphagia
HP:0007185	Loss of consciousness
HP:0011968	Feeding difficulties
HP:0012051	Reactive hypoglycemia
HP:0012759	Neurodevelopmental abnormality
HP:0030796	Increased C-peptide level
HP:0031084	Excessive insulin response to glucagon test
HP:0031224	Diffuse pancreatic islet hyperplasia
HP:0040299	Decreased circulating free fatty acid level

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002395_94	Mean platelet volume	4.000000e-11

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs586773	UCP2		0.00	0
rs591758	UCP2		0.00	0
rs649446	UCP2		0.00	0
rs655717	DNAJB13, UCP2		0.00	0
rs659366	UCP2		0.00	0
rs660339	UCP2		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — Mitochondrial uncoupling proteins

CTD chemical–gene interactions

103 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ochratoxin A	affects cotreatment, increases expression, decreases expression	4
Rosiglitazone	increases reaction, increases expression	4
Cisplatin	affects cotreatment, increases expression, decreases expression, affects response to substance	4
Benzo(a)pyrene	increases expression, increases methylation, decreases methylation	3
Doxorubicin	increases expression, affects reaction, decreases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
Valproic Acid	affects expression, decreases expression, increases expression	3
beauvericin	affects cotreatment, increases expression, decreases expression	2
bisphenol A	decreases expression, increases expression	2
cobaltous chloride	decreases expression	2
enniatins	affects cotreatment, increases expression, decreases expression	2
Air Pollutants	increases abundance, increases expression	2
Atrazine	decreases expression, increases expression	2
Cadmium	decreases expression, increases abundance, increases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Indomethacin	affects cotreatment, increases expression	2
Plant Extracts	affects cotreatment, increases expression, decreases expression, affects response to substance	2
Quercetin	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tretinoin	decreases expression, increases expression	2
1-Methyl-4-phenylpyridinium	affects reaction, decreases reaction, affects expression, decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
dicrotophos	increases expression	1
bufotalin	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	increases expression	1

Cellosaurus cell lines

9 cell lines: 9 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C7Z3	HAP1 UCP2 (-) 1	Cancer cell line	Male
CVCL_C7Z4	HAP1 UCP2 (-) 2	Cancer cell line	Male
CVCL_D1ZJ	Abcam A-549 UCP2 KO	Cancer cell line	Male
CVCL_D2DK	Abcam HCT 116 UCP2 KO	Cancer cell line	Male
CVCL_D2PE	Abcam THP-1 UCP2 KO	Cancer cell line	Male
CVCL_D4FP	1321N1-UCP2-KO-c3	Cancer cell line	Male
CVCL_D4FQ	1321N1-UCP2-KO-c5	Cancer cell line	Male
CVCL_E2NB	HAP1 UCP2 (-) 3	Cancer cell line	Male
CVCL_E2NC	HAP1 UCP2 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02971202	PHASE1	COMPLETED	Contribution of Hyperinsulinemia vs. Hyperglycemia to Insulin Resistance in Type 1 Diabetes and Maturity Onset Diabetes of the Young, Type 2 (MODY2)