Affinage

UCP2

Dicarboxylate carrier SLC25A8 · UniProt P55851

Length
309 aa
Mass
33.2 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UCP2 is a mitochondrial inner-membrane transporter that, rather than acting solely as a proton-leak uncoupler, exports C4 metabolites—malate, oxaloacetate, and aspartate—in exchange for phosphate plus a proton, a transport activity demonstrated directly by reconstitution in lipid vesicles (PMID:24395786). By shunting these substrates out of mitochondria, UCP2 limits oxidation of acetyl-CoA-generating fuels such as glucose, promotes glycolysis, and enhances glutaminolysis (PMID:24395786, PMID:22085932, PMID:36275699), thereby positioning the protein as a node controlling cellular redox balance and metabolic fate. This substrate-routing function supports cytosolic NADPH production and glutathione-based antioxidant defense: in KRAS-mutant pancreatic adenocarcinoma, UCP2-mediated aspartate efflux sustains NADPH/GSH and suppresses ROS to drive tumor growth (PMID:33230296), and UCP2 loss in colon tumors limits NADPH availability and enhances tumorigenesis (PMID:31461648). Through its control of ROS, UCP2 governs diverse downstream programs—AMPK activation with HIF-1α suppression and restraint of malignant phenotypes (PMID:24853548), AKT/PFKFB2-driven glycolysis (PMID:29221144), ROS-dependent stabilization of Yap during neurogenesis (PMID:28276603), and pancreatic progenitor expansion via NRF2/AKT signaling (PMID:29079704). UCP2 also modulates autophagy and mitophagy in an ROS-dependent manner (PMID:23124112, PMID:34625529, PMID:33708886) and shapes innate immunity by supporting FASN-dependent lipid synthesis for NLRP3 inflammasome activation in macrophages (PMID:25574840) and by driving the mtDNA/STING autoinflammatory axis in β cells (PMID:40707441). Physiologically, UCP2 regulates hormone secretion from pancreatic islets—uncoupling and tuning ROS to control glucagon release from α cells (PMID:18701716, PMID:23434936)—and acts as a KLF2-controlled, shear-stress-responsive endothelial gene that suppresses FoxO1-driven inflammation via AMPK to protect against atherogenesis (PMID:35899624). UCP2 localizes to mitochondria (PMID:10849580), and its abundance is set both transcriptionally and translationally, including hnRNPK-mediated control of UCP2 protein levels through its 3'-UTR (PMID:15485813).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 Medium

    Before its function was understood, the genomic and transcriptional architecture of UCP2 had to be defined to enable regulatory studies.

    Evidence Genomic cloning, primer extension, and promoter-reporter assays in multiple cell lines for the mouse gene

    PMID:9710252

    Open questions at the time
    • Does not identify the trans-acting factors binding the positive regulatory region
    • Promoter analysis in mouse only
  2. 2000 Medium

    Establishing UCP2's subcellular compartment was prerequisite to any mitochondrial mechanism, confirmed by direct imaging.

    Evidence Transfection of human UCP2 into CHO cells with confocal immunofluorescence

    PMID:10849580

    Open questions at the time
    • Single localization method in an overexpression system
    • Does not address submitochondrial topology
  3. 2001 Medium

    An early functional question—whether UCP2 can actually uncouple respiration—was answered in vivo in skeletal muscle.

    Evidence Intramuscular plasmid gene transfer in rats with membrane potential readouts

    PMID:11244460

    Open questions at the time
    • Overexpression may force non-physiological uncoupling
    • Does not distinguish proton leak from metabolite transport
  4. 2008 High

    Cell-type-resolved analysis showed UCP2 tunes islet hormone secretion, linking mitochondrial coupling to glucagon physiology.

    Evidence UCP2-/- mice with mitochondrial membrane potential, ATP/O, and glucagon secretion assays comparing alpha- and beta-cells

    PMID:18701716

    Open questions at the time
    • Mechanism connecting coupling efficiency to secretory machinery not detailed
    • Whole-body KO does not isolate alpha-cell-autonomous effects
  5. 2004 Medium

    UCP2 abundance was shown to be set post-transcriptionally, revealing translational control as a regulatory layer.

    Evidence Yeast three-hybrid screen, polysome fractionation, and hnRNPK overexpression tracking UCP2 protein vs mRNA

    PMID:15485813

    Open questions at the time
    • Single lab; mechanism of insulin-induced translational activation not fully resolved
    • Physiological importance in vivo untested
  6. 2014 High

    The defining mechanistic advance recast UCP2 as a C4-metabolite exporter rather than a simple uncoupler, explaining how it reroutes glucose vs glutamine metabolism.

    Evidence Reconstitution in lipid vesicles with transport assay plus siRNA silencing and metabolite profiling in HepG2 cells

    PMID:24395786

    Open questions at the time
    • Relative in vivo contribution of transport vs residual proton leak not quantified
    • Structural basis of substrate selectivity unresolved
  7. 2013 High

    Alpha-cell-specific deletion tied UCP2-controlled ROS to stimulus-secretion coupling and counter-regulatory glucagon release during hypoglycemia.

    Evidence Alpha-cell-specific KO mice with hypoglycemia challenge, ROS and secretion assays, validated by genipin in human islets

    PMID:23434936

    Open questions at the time
    • Genipin is not UCP2-selective
    • Link between ROS and exocytotic machinery not molecularly defined
  8. 2015 High

    UCP2 was placed in innate immune control by coupling its activity to FASN-dependent lipid synthesis needed for NLRP3 inflammasome activation.

    Evidence UCP2-deficient mice, FASN knockdown and inhibitors, caspase-1 and cytokine assays establishing UCP2-FASN epistasis

    PMID:25574840

    Open questions at the time
    • How metabolite transport drives FASN upregulation mechanistically not shown
    • Relationship to UCP2's antioxidant role in same cells unclear
  9. 2014 Medium

    Independent cancer studies linked UCP2 substrate routing to AMPK/HIF-1α signaling and the glycolytic phenotype.

    Evidence UCP2 overexpression in cancer lines with AMPK, HIF-1α, and tumor phenotype readouts

    PMID:24853548

    Open questions at the time
    • Causal order between metabolic shift and AMPK/HIF-1α not fully dissected
    • Single overexpression context
  10. 2017 Medium

    Multiple developmental and signaling studies converged on UCP2-controlled ROS as the effector regulating Yap, NRF2/AKT, and progenitor fate.

    Evidence Conditional KO/knockdown in neocortex and pancreas with ROS, Yap, NRF2 readouts and genetic/antioxidant rescue; AKT/PFKFB2 epistasis in skin cells with 13C tracing

    PMID:28276603 PMID:29079704 PMID:29221144

    Open questions at the time
    • Whether ROS effects stem from metabolite transport or residual uncoupling not resolved per study
    • Tissue specificity of downstream effectors not generalized
  11. 2020 High

    UCP2-dependent aspartate efflux was shown to fuel cytosolic NADPH/glutathione and ROS control required for KRAS-mutant PDAC growth, extending the C4 transport model to cancer redox biology.

    Evidence siRNA/shRNA silencing in PDAC lines, metabolic flux, redox assays, and xenografts

    PMID:33230296

    Open questions at the time
    • Generalizability beyond KRAS-mutant context not addressed
    • Does not test whether transport-dead UCP2 abolishes the effect
  12. 2019 Medium

    In vivo cancer models showed UCP2 loss impairs NADPH-dependent antioxidant defense and promotes intestinal tumorigenesis, and microglial UCP2 was tied to diet-induced obesity and hypothalamic inflammation.

    Evidence Ucp2 KO in AOM/DSS and ApcMin/+ models with NADPH/GSH readouts; microglia-specific conditional KO with HFD and mitochondrial dynamics imaging

    PMID:31461648 PMID:31495690

    Open questions at the time
    • Tissue-of-origin cell-autonomy in tumor models not fully isolated
    • Connection between microglial mitochondrial dynamics and feeding circuits incompletely mapped
  13. 2022 High

    UCP2 was identified as a KLF2-controlled, shear-stress-responsive endothelial gene that restrains FoxO1 inflammation via AMPK and protects against atherosclerosis, and as a metabolic oxygen sensor regulating cardiomyocyte cell cycle through acetyl-CoA/histone acetylation.

    Evidence KLF2 ChIP on UCP2 promoter, EC-specific KO, AAV overexpression, RNA-seq, atherosclerosis model; UCP2-KO cardiomyocytes under hypoxia with acetyl-CoA and histone acetylation assays

    PMID:35771638 PMID:35899624

    Open questions at the time
    • Direct biochemical link between transport activity and AMPK phosphorylation not established
    • How UCP2 senses oxygen mechanistically remains open
  14. 2022 Medium

    Isotopic tracing confirmed UCP2 exports malate to sustain TCA flux in glutamine-dependent leukemia, reinforcing the transporter model across cancer types.

    Evidence UCP2 siRNA in T-ALL lines with 13C tracing, respiration, and glycolysis assays

    PMID:36275699

    Open questions at the time
    • Single lineage tested
    • Does not measure direct transport vs indirect metabolic adaptation
  15. 2025 Medium

    Recent work extended UCP2 into autophagy/mitophagy control and a β-cell mtDNA/STING autoinflammatory axis, integrating its redox role with cell survival and inflammation.

    Evidence Gain/loss-of-function with ROS, autophagy flux, SIRT3, mtDNA and STING readouts across endothelial, renal, cardiac, and β-cell systems, including genipin and nanomedicine targeting in T2DM models

    PMID:23124112 PMID:33708886 PMID:34625529 PMID:38175638 PMID:40707441

    Open questions at the time
    • Genipin specificity limits causal attribution to UCP2
    • Whether mtDNA release is a direct consequence of transport activity unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how UCP2's biochemically defined C4-metabolite transport activity mechanistically generates its many downstream signaling outputs (AMPK, HIF-1α, Yap, STING) and whether residual proton-leak uncoupling contributes independently.
  • No transport-dead mutant used to separate transport from uncoupling in signaling phenotypes
  • No high-resolution structure defining substrate selectivity
  • Quantitative in vivo flux contribution of UCP2 transport not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0140104 molecular carrier activity 2
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 3
Partners
HNRNPK

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 UCP2 functions as a metabolite transporter that exchanges malate, oxaloacetate, and aspartate for phosphate plus a proton across the mitochondrial membrane, thereby exporting C4 compounds out of mitochondria. This limits oxidation of acetyl-CoA-producing substrates (e.g., glucose) and enhances glutaminolysis. Reconstitution of UCP2 in lipid vesicles directly demonstrated this transport activity. Reconstitution in lipid vesicles (transport assay), siRNA silencing in HepG2 cells with metabolite profiling, membrane potential and ATP:ADP ratio measurements Proceedings of the National Academy of Sciences of the United States of America High 24395786
2020 In KRAS-mutant pancreatic ductal adenocarcinoma cells, UCP2 catalyses mitochondrial aspartate efflux required for cytosolic NADPH production via the rewired glutamine metabolic pathway. UCP2 silencing decreased glutaminolysis, lowered NADPH/NADP+ and glutathione/GSSG ratios, raised ROS, and strongly suppressed KRASmut PDAC growth in vitro and in vivo. siRNA/shRNA silencing of UCP2 in PDAC cell lines, metabolic flux analysis, ROS measurements, xenograft mouse models Nature metabolism High 33230296
2011 UCP2 prevents mitochondrial glucose oxidation and facilitates glycolysis via a substrate-shunting mechanism in human pluripotent stem cells. Ectopic UCP2 expression perturbs the metabolic transition during differentiation and impairs hPSC differentiation. UCP2 repression is required for full differentiation potential. Ectopic UCP2 overexpression in hPSCs, siRNA knockdown, metabolic flux measurements (O2 consumption, glycolysis), differentiation assays The EMBO journal High 22085932
2015 UCP2 regulates NLRP3 inflammasome activation through stimulation of fatty acid (lipid) synthesis via fatty acid synthase (FASN) upregulation in macrophages. UCP2-deficient macrophages showed impaired lipid synthesis, downregulated FASN, and suppressed NLRP3-mediated caspase-1 activation and IL-1β/IL-18 production. FASN inhibition phenocopied UCP2 deficiency. UCP2-deficient mice, shRNA knockdown of FASN, chemical inhibitors (C75, cerulenin), LPS challenge, caspase-1 activity assay, cytokine measurement The Journal of clinical investigation High 25574840
2019 Selective microglial deletion of UCP2 prevented HFD-induced changes in mitochondrial dynamics and function, microglia activation, and hypothalamic inflammation, protecting mice from diet-induced obesity with decreased feeding and increased energy expenditure. Microglial-specific Ucp2 conditional knockout mice, HFD feeding, mitochondrial dynamics imaging, synaptic input analysis, POMC neuron activation assays Cell metabolism High 31495690
2008 UCP2 is expressed at significantly higher levels in pancreatic alpha-cells than beta-cells, where it causes greater mitochondrial uncoupling and lower oxidative phosphorylation efficiency. Reducing UCP2 activity in alpha-cells increased ATP synthesis and altered glucagon secretion in response to low glucose. UCP2-/- mice, mitochondrial membrane potential measurements, ATP/O ratio, glucagon secretion assays in vitro and in vivo Proceedings of the National Academy of Sciences of the United States of America High 18701716
2013 Alpha-cell-specific UCP2 deletion impairs blood glucose recovery during hypoglycemia due to attenuated glucagon secretion. UCP2-deleted alpha-cells have higher intracellular ROS from enhanced mitochondrial coupling, which disrupts stimulus-secretion coupling. UCP2 inhibitor genipin on murine and human islets phenocopied the genetic deletion. Alpha-cell-specific UCP2 knockout mice, hypoglycemia challenge, ROS measurement, glucagon secretion assay, genipin pharmacology on murine and human islets Diabetes High 23434936
2022 KLF2 (Krüppel-like factor 2) mediates fluid shear stress-dependent regulation of UCP2 expression in endothelial cells by directly binding the UCP2 promoter. EC-specific Ucp2 deletion promotes atherogenesis; UCP2 suppresses FoxO1-driven proinflammatory transcription via AMPK phosphorylation. Shear stress simulation, KLF2 ChIP on UCP2 promoter, EC-specific Ucp2 KO mice, adeno-associated virus-mediated UCP2 overexpression, RNA-seq, carotid atherosclerosis model Circulation research High 35899624
2004 The RNA-binding protein hnRNPK binds ucp2 mRNA through sites in the 3'-untranslated region and associates with polysome-coated mitochondria. Exogenous hnRNPK augments insulin-induced mitochondrial UCP2 protein levels without a corresponding increase in ucp2 mRNA, indicating translational regulation. Yeast three-hybrid screen, polysome fractionation, mitochondrial isolation and Western blot, hnRNPK overexpression The Journal of biological chemistry Medium 15485813
2001 In vivo muscle gene transfer of UCP2 cDNA increased UCP2 protein 3.6-fold and caused a significant reduction in mitochondrial membrane potential, demonstrating that UCP2 can uncouple respiration when expressed in skeletal muscle mitochondria. Intramuscular plasmid injection in rats, Western blot for UCP2 protein, spectrofluorometry and flow cytometry for mitochondrial membrane potential International journal of obesity and related metabolic disorders Medium 11244460
2005 LPS injection in rats recruits UCP2 protein to liver mitochondria (3-fold increase in 3H-GTP binding sites), causes lower mitochondrial membrane potential in hepatocytes, and increases H2O2 production inhibitable by GDP, indicating that recruited UCP2 causes mild uncoupling sufficient to reduce mitochondrial ROS production. In vivo LPS injection, 3H-GTP binding assay, real-time RT-PCR, Western blot, JC1 fluorescence for membrane potential, H2O2 production assay The international journal of biochemistry & cell biology Medium 15694840
2000 Transfected human UCP2 localizes exclusively to mitochondria in CHO cells, establishing its subcellular compartment by direct imaging. Transfection of human UCP2 into CHO cells, confocal immunofluorescence microscopy International journal of obesity and related metabolic disorders Medium 10849580
2002 PPARα activation in INS-1 insulinoma cells doubles UCP2 expression and reduces glucose-stimulated insulin secretion; this suppression is prevented by CPT-I inhibitor etomoxir, linking PPARα-stimulated fatty acid oxidation through UCP2 to impaired beta-cell insulin secretion. Adenovirus-mediated PPARα overexpression, clofibric acid treatment, CPT-I inhibitor etomoxir, insulin secretion assay, UCP2 mRNA measurement Journal of lipid research Medium 12032169
2014 UCP2 overexpression in cancer cells restores balance toward oxidative phosphorylation, increases AMPK signaling, downregulates HIF-1α expression, and represses malignant phenotypes. UCP2 acted by controlling substrate routing to mitochondria rather than via membrane potential uncoupling. UCP2 overexpression in cancer cell lines, AMPK signaling analysis, HIF-1α expression, metabolic enzyme expression, tumor phenotype assays Cancer research Medium 24853548
2017 UCP2 overexpression activates PFKFB2 via an AKT-dependent signaling pathway in skin cells, elevating fructose-2,6-bisphosphate, PFK-1 activity, glucose uptake and lactate production, promoting glycolysis and cell transformation. PFKFB2 inhibition reversed UCP2-mediated transformation. UCP2 overexpression in JB6 skin cells, PFKFB2 knockdown/inhibition, 13C glucose tracing, AKT inhibition, cell transformation assay Oncotarget Medium 29221144
2017 UCP2 controls embryonic neurogenesis by inhibiting ROS production; when UCP2 is knocked down or conditionally deleted in developing neocortex, ROS increases, Yap protein accumulates (via decreased ubiquitin-proteasome degradation), progenitor proliferation increases and differentiation decreases. Yap downregulation rescues the UCP2-deficiency phenotype. UCP2 knockdown and conditional KO in mouse embryonic brain, ROS measurement, Yap protein quantitation, Yap genetic rescue experiment Stem cells (Dayton, Ohio) Medium 28276603
2017 UCP2 controls pancreas development by regulating ROS levels: Ucp2-/- fetuses show increased pancreas size, more α- and β-cells, and expanded PDX1+ progenitors associated with increased nuclear NRF2 translocation (indicating increased ROS) and AKT phosphorylation. N-acetylcysteine administration to pregnant Ucp2-/- mice alleviated the phenotype. Ucp2 knockout mice, fetal pancreas analysis, NRF2 nuclear translocation assay, AKT phosphorylation, NAC antioxidant rescue Diabetes Medium 29079704
2019 UCP2 deficiency in colon tumors increases oxidized glutathione and protein oxidation, alters glycolytic pathways, and promotes phospholipid synthesis, limiting NADPH availability for antioxidant defense. UCP2 loss enhances colon and intestinal tumorigenesis in AOM/DSS and ApcMin/+ mouse models. Ucp2 KO in AOM/DSS and ApcMin/+ mouse cancer models, NADPH/NADP+ measurement, glutathione oxidation, phospholipid synthesis assays, tumor quantification Cell reports Medium 31461648
2022 UCP2 acts as a metabolic oxygen sensor in cardiomyocytes: under moderate hypoxia, UCP2 expression increases, promotes a glycolytic shift, increases acetyl-CoA levels and histone acetylation, and promotes cardiomyocyte cell cycle activity. UCP2-KO mice under hypoxia show reduced cell cycle activity, increased fibrosis and DNA damage. UCP2-KO mouse model, neonatal rat ventricular myocyte culture under hypoxia, acetyl-CoA measurement, histone acetylation assay, cell cycle analysis, mitochondrial membrane potential, mtDNA quantification JCI insight Medium 35771638
2015 Inhibition or deletion of FABP4/aP2 in macrophages elevates intracellular free fatty acids and upregulates UCP2, reducing ER stress and ROS. Silencing UCP2 in FABP4-deficient macrophages negates the protective effect and increases ER stress, placing UCP2 downstream of FABP4/FFA equilibrium in regulating macrophage oxidative stress. FABP4 KO macrophages, FABP4 pharmacologic inhibition (HTS01037), UCP2 siRNA rescue, mitochondrial protein carbonylation, ROS measurement, ER stress marker expression Molecular and cellular biology Medium 25582199
2017 FABP4 regulates macrophage redox signaling and NLRP3 inflammasome activation via control of UCP2 expression: FABP4-/- macrophages show reduced mitochondrial protein oxidation, attenuated mtUPR, reduced NLRP3/caspase-1 and IL-1β secretion; these effects are partially rescued by UCP2 silencing in FABP4-null macrophages. FABP4-/- macrophages, UCP2 silencing rescue, mitochondrial protein cysteine oxidation, mtUPR markers (HSP60, ClpP, LonP1), caspase-1 cleavage, IL-1β secretion Molecular and cellular biology Medium 27795298
2008 Upregulation of UCP2 in NASH liver mitochondria induces increased proton leak, which correlates with increased mitochondrial H2O2 production and decreased hepatic ATP content independent of ATPase dysfunction. Mitochondrial isolation from NASH human and rat liver, proton leak kinetics, H2O2 production assay, HNE-protein adduct measurement, UCP2 protein expression (Western blot), ATP measurement Gut Medium 18308829
2012 UCP2 inhibition (by genipin or siRNA) in pancreatic adenocarcinoma cells increases ROS production, triggers ROS-dependent nuclear translocation of GAPDH, formation of autophagosomes, and LC3-II expression. UCP2 overexpression reduces basal autophagy. Autophagy induced by UCP2 inhibition mediates ROS-dependent cell death. Genipin treatment, UCP2 siRNA knockdown, UCP2 overexpression, GAPDH localization assay, autophagosome formation, LC3-II Western blot, autophagy inhibitors (chloroquine, 3-MA), NAC ROS scavenging Biochimica et biophysica acta Medium 23124112
2021 UCP2 mediates the interaction between high-salt-induced ROS and autophagy/mitophagy to preserve cell viability in endothelial and renal tubular cells; UCP2 silencing reduces autophagy and mitophagy flux, while UCP2 overexpression increases them. Excessive ROS accumulation upon UCP2 silencing turns off autophagy. UCP2 siRNA silencing, UCP2 overexpression, autophagy flux assay, mitophagy markers, ROS measurement, Tat-Beclin 1 autophagy inducer rescue in UCP2-silenced cells Cell death & disease Medium 34625529
2024 UCP2 overexpression in retinal endothelial cells protects against hyperglycemia-induced oxidative stress and senescence by maintaining NAD+ levels and thereby promoting SIRT3 expression and activity; selective SIRT3 inhibition (3-TYP) abolishes the UCP2-mediated protective effect. Adenovirus-mediated UCP2 overexpression and knockdown in HRECs, NAD+ measurement, SIRT3 activity assay, 3-TYP inhibitor epistasis, ROS flow cytometry, SA-β-gal senescence assay Investigative ophthalmology & visual science Medium 38175638
2025 In pancreatic β cells under T2DM conditions, IL-1β drives autoinflammation through the UCP2/mtDNA/STING axis: UCP2 inhibition reduces mtDNA release and STING activation, thereby eliminating β-cell autoinflammation. UCP2 inhibitor genipin, nanomedicine (Mito-G) targeting β-cell mitochondria, STING pathway analysis, mtDNA quantitation, IL-1β stimulation model, in vivo T2DM mouse model Nature communications Medium 40707441
2021 UCP2 controls autophagy in cardiomyocytes during sepsis via AMPK: UCP2 silencing reduces AMPK phosphorylation (correlated with changes in upstream kinases pLKB1 and CAMKK2), limits autophagy protein upregulation, and aggravates mitochondrial injury; AMPK agonist AICAR rescues UCP2-KO cardiac phenotype. UCP2 KO mice (CLP sepsis model), UCP2 siRNA in H9C2 cells, AICAR treatment, AMPK phosphorylation, LKB1/CAMKK2 expression, autophagy protein assay (Beclin-1, LC3-I/II, pULK1) Annals of translational medicine Medium 33708886
2022 UCP2 silencing in T-ALL cell lines decreases malate export from mitochondria, disrupting TCA cycle flux and impairing cell proliferation. T-ALL cells relying on glutamine-dependent oxidative metabolism redirect to glycolysis upon UCP2 silencing. UCP2 siRNA in T-ALL cell lines, 13C metabolic tracing, mitochondrial respiration measurement, glycolysis assay, lipid synthesis measurement Frontiers in immunology Medium 36275699
1998 The mouse UCP2 gene spans ~6.3 kb with 8 exons and 7 introns. The promoter lacks TATA and CAAT boxes and is GC-rich; a region from -160 to -678 bp exhibits strong positive regulatory activity. A single transcription start site 369 bp upstream of the translational start was identified. Genomic cloning, primer extension analysis, promoter-reporter transfection assays in 6 cell lines FEBS letters Medium 9710252
2004 UCP2 overexpression in 3T3-L1 adipocytes reduces mitochondrial membrane potential and ATP production, increases caspase expression, decreases Bcl-2/Bax ratio, and induces apoptosis. Physiological doses of 1,25-(OH)2-D3 restore mitochondrial membrane potential and protect against UCP2-induced apoptosis via suppression of mitochondrial Ca2+. UCP2 overexpression in 3T3-L1 cells, mitochondrial membrane potential measurement, ATP assay, caspase and Bcl-2/Bax expression, Ca2+ measurement, 1,25-(OH)2-D3 dose-response FASEB journal Low 15231722
2001 Insulin dose-dependently increases UCP2 mRNA expression in rat skeletal muscle in vitro, independent of glucose uptake. AICAR (AMPK activator) mimics this increase, suggesting AMPK as a mediator of contraction-induced UCP2 upregulation. Isolated rat EDL muscle in vitro incubation, insulin dose-response, electrical contraction, AICAR treatment, RT-PCR for UCP2/UCP3 mRNA Biochemical and biophysical research communications Low 11322761
2021 Chronic hypoxanthine treatment upregulates UCP2 in skeletal muscle, leading to decreased energy substrate storage and enhanced glycolysis causing muscular fatigue. Muscle-specific UCP2 knockout via AAV reversed hypoxanthine-induced effects. Dietary hypoxanthine supplementation in mice, intra-muscle AAV-mediated UCP2 KO, exercise performance test, glycolysis and energy storage assays Frontiers in physiology Low 33746782

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. The Biochemical journal 640 10620491
2011 UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. The EMBO journal 410 22085932
2014 UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation. Proceedings of the National Academy of Sciences of the United States of America 338 24395786
1998 Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima indians. Human molecular genetics 251 9700198
2019 Matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway. Acta pharmaceutica Sinica. B 227 31384530
2015 UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis. The Journal of clinical investigation 215 25574840
2019 Microglial UCP2 Mediates Inflammation and Obesity Induced by High-Fat Feeding. Cell metabolism 197 31495690
2003 The 'novel' 'uncoupling' proteins UCP2 and UCP3: what do they really do? Pros and cons for suggested functions. Experimental physiology 195 12525856
2011 Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism. Trends in molecular medicine 181 21917523
2008 Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury. Gut 176 18308829
2002 UCP2 and UCP3 in muscle controlling body metabolism. The Journal of experimental biology 152 12110661
2006 The emerging functions of UCP2 in health, disease, and therapeutics. Antioxidants & redox signaling 151 16487034
2013 UCP2, a mitochondrial protein regulated at multiple levels. Cellular and molecular life sciences : CMLS 147 23807210
2009 UCP2, not a physiologically relevant uncoupler but a glucose sparing switch impacting ROS production and glucose sensing. Biochimica et biophysica acta 115 19413946
2009 The polymorphisms of UCP2 and UCP3 genes associated with fat metabolism, obesity and diabetes. Obesity reviews : an official journal of the International Association for the Study of Obesity 113 19413708
2020 KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth. Nature metabolism 110 33230296
2014 Mitochondrial UCP2 in the central regulation of metabolism. Best practice & research. Clinical endocrinology & metabolism 102 25256770
2010 Uncoupling protein UCP2: when mitochondrial activity meets immunity. FEBS letters 101 20227410
2015 Uncoupling lipid metabolism from inflammation through fatty acid binding protein-dependent expression of UCP2. Molecular and cellular biology 85 25582199
2012 UCP2 inhibition triggers ROS-dependent nuclear translocation of GAPDH and autophagic cell death in pancreatic adenocarcinoma cells. Biochimica et biophysica acta 83 23124112
2004 Role of uncoupling protein 2 (UCP2) expression and 1alpha, 25-dihydroxyvitamin D3 in modulating adipocyte apoptosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 80 15231722
2017 FABP4/aP2 Regulates Macrophage Redox Signaling and Inflammasome Activation via Control of UCP2. Molecular and cellular biology 79 27795298
2018 Melatonin Balance the Autophagy and Apoptosis by Regulating UCP2 in the LPS-Induced Cardiomyopathy. Molecules (Basel, Switzerland) 76 29547569
2013 TRPV1-mediated UCP2 upregulation ameliorates hyperglycemia-induced endothelial dysfunction. Cardiovascular diabetology 75 23607427
2011 The role of uncoupling protein 2 (UCP2) on the development of type 2 diabetes mellitus and its chronic complications. Arquivos brasileiros de endocrinologia e metabologia 73 21779625
2019 UCP2 ameliorates mitochondrial dysfunction, inflammation, and oxidative stress in lipopolysaccharide-induced acute kidney injury. International immunopharmacology 72 30952098
2002 PPARalpha suppresses insulin secretion and induces UCP2 in insulinoma cells. Journal of lipid research 72 12032169
2014 Mitochondrial retrograde signaling mediated by UCP2 inhibits cancer cell proliferation and tumorigenesis. Cancer research 71 24853548
1999 Skeletal muscle UCP2 and UCP3 expression in trained and untrained male subjects. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 71 10490803
2022 Endothelial UCP2 Is a Mechanosensitive Suppressor of Atherosclerosis. Circulation research 67 35899624
2015 Indoxyl sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting the AMPK/UCP2 signaling pathway. Toxicology letters 64 25703824
2013 UCP2 regulates the glucagon response to fasting and starvation. Diabetes 61 23434936
2008 UCP2 is highly expressed in pancreatic alpha-cells and influences secretion and survival. Proceedings of the National Academy of Sciences of the United States of America 61 18701716
2001 Insulin and contraction directly stimulate UCP2 and UCP3 mRNA expression in rat skeletal muscle in vitro. Biochemical and biophysical research communications 58 11322761
2019 UCP2 gene polymorphisms in obesity and diabetes, and the role of UCP2 in cancer. FEBS letters 57 31330574
2017 COL1A1, PRPF40A, and UCP2 correlate with hypoxia markers in non-small cell lung cancer. Journal of cancer research and clinical oncology 57 28258342
2017 Identification of a fatty acid binding protein4-UCP2 axis regulating microglial mediated neuroinflammation. Molecular and cellular neurosciences 54 28214555
1999 UCP1: the original uncoupling protein--and perhaps the only one? New perspectives on UCP1, UCP2, and UCP3 in the light of the bioenergetics of the UCP1-ablated mice. Journal of bioenergetics and biomembranes 51 10653476
2017 miRNA-133a-UCP2 pathway regulates inflammatory bowel disease progress by influencing inflammation, oxidative stress and energy metabolism. World journal of gastroenterology 50 28104982
2020 UCP2-induced hypoxia promotes lipid accumulation and tubulointerstitial fibrosis during ischemic kidney injury. Cell death & disease 49 31932578
2018 UCP2-dependent improvement of mitochondrial dynamics protects against acute kidney injury. The Journal of pathology 48 30426490
2004 Links between fatty acids and expression of UCP2 and UCP3 mRNAs. FEBS letters 48 15196910
2019 UCP2 protect the heart from myocardial ischemia/reperfusion injury via induction of mitochondrial autophagy. Journal of cellular biochemistry 47 31081966
2019 UCP2 promotes proliferation and chemoresistance through regulating the NF-κB/β-catenin axis and mitochondrial ROS in gallbladder cancer. Biochemical pharmacology 47 31811866
2021 An interplay between UCP2 and ROS protects cells from high-salt-induced injury through autophagy stimulation. Cell death & disease 46 34625529
2021 Exercise training mitigates ER stress and UCP2 deficiency-associated coronary vascular dysfunction in atherosclerosis. Scientific reports 42 34326395
2019 UCP2 Deficiency Increases Colon Tumorigenesis by Promoting Lipid Synthesis and Depleting NADPH for Antioxidant Defenses. Cell reports 40 31461648
2022 UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control. International journal of molecular sciences 37 36499405
2018 Effects of resveratrol on regulation on UCP2 and cardiac function in diabetic rats. Journal of physiology and biochemistry 37 30225723
2015 UCP2-related mitochondrial pathway participates in oroxylin A-induced apoptosis in human colon cancer cells. Journal of cellular physiology 37 25251374
2022 Genipin, an Inhibitor of UCP2 as a Promising New Anticancer Agent: A Review of the Literature. International journal of molecular sciences 36 35628447
2019 UCP2 alleviates tubular epithelial cell apoptosis in lipopolysaccharide-induced acute kidney injury by decreasing ROS production. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 36 31071510
2017 UCP2 overexpression enhanced glycolysis via activation of PFKFB2 during skin cell transformation. Oncotarget 36 29221144
2023 Malvidin alleviates mitochondrial dysfunction and ROS accumulation through activating AMPK-α/UCP2 axis, thereby resisting inflammation and apoptosis in SAE mice. Frontiers in pharmacology 35 36699054
2024 UCP2, a Member of the Mitochondrial Uncoupling Proteins: An Overview from Physiological to Pathological Roles. Biomedicines 34 38927514
2023 Exploring a new mechanism between lactate and VSMC calcification: PARP1/POLG/UCP2 signaling pathway and imbalance of mitochondrial homeostasis. Cell death & disease 33 37679327
2004 Heterogeneous nuclear ribonucleoprotein K enhances insulin-induced expression of mitochondrial UCP2 protein. The Journal of biological chemistry 33 15485813
2019 Upregulation of UCP2 Expression Protects against LPS-Induced Oxidative Stress and Apoptosis in Cardiomyocytes. Oxidative medicine and cellular longevity 32 31182990
2017 Mitochondrial Protein UCP2 Controls Pancreas Development. Diabetes 31 29079704
2014 Antioxidant and regulatory role of mitochondrial uncoupling protein UCP2 in pancreatic beta-cells. Physiological research 31 24564667
2018 Genipin Reverses HFD-Induced Liver Damage and Inhibits UCP2-Mediated Pyroptosis in Mice. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 29 30235442
1998 Genomic organization and promoter function of the mouse uncoupling protein 2 (UCP2) gene. FEBS letters 29 9710252
2017 UCP2 Regulates Embryonic Neurogenesis via ROS-Mediated Yap Alternation in the Developing Neocortex. Stem cells (Dayton, Ohio) 28 28276603
2002 Uncoupling protein 2 (UCP2) lowers alcohol sensitivity and pain threshold. Biochemical pharmacology 28 12147287
1999 Effect of thiazolidinediones on expression of UCP2 and adipocyte markers in human PAZ6 adipocytes. Diabetologia 27 10333043
2003 Cardiac UCP2 expression and myocardial oxidative metabolism during acute septic shock in the rat. Shock (Augusta, Ga.) 26 12785014
2000 Depot-related and thiazolidinedione-responsive expression of uncoupling protein 2 (UCP2) in human adipocytes. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 26 10849580
2025 Irisin regulates oxidative stress and mitochondrial dysfunction through the UCP2-AMPK pathway in prion diseases. Cell death & disease 25 39900919
2018 Overexpressed UCP2 regulates mitochondrial flashes and reverses lipopolysaccharide-induced cardiomyocytes injury. American journal of translational research 25 29887950
2022 UCP2 modulates cardiomyocyte cell cycle activity, acetyl-CoA, and histone acetylation in response to moderate hypoxia. JCI insight 24 35771638
2021 Hypoxanthine Induces Muscular ATP Depletion and Fatigue via UCP2. Frontiers in physiology 23 33746782
2017 UCP2 and PLIN1 Expression Affects the Resting Metabolic Rate and Weight Loss on Obese Patients. Obesity surgery 23 27376365
2001 UCP2 muscle gene transfer modifies mitochondrial membrane potential. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 23 11244460
1999 Regulation of UCP2 and UCP3 by muscle disuse and physical activity in tetraplegic subjects. Diabetologia 23 10440124
2021 Activation of UCP2 by anethole trithione suppresses neuroinflammation after intracerebral hemorrhage. Acta pharmacologica Sinica 22 34183754
2021 The effects of UCP2 on autophagy through the AMPK signaling pathway in septic cardiomyopathy and the underlying mechanism. Annals of translational medicine 21 33708886
2019 UCP2 regulates cholangiocarcinoma cell plasticity via mitochondria-to-AMPK signals. Biochemical pharmacology 21 31085159
2016 Mitochondrial Uncoupling Protein 2 (UCP2) Regulates Retinal Ganglion Cell Number and Survival. Journal of molecular neuroscience : MN 21 26846222
2021 UCP2 as a Potential Biomarker for Adjunctive Metabolic Therapies in Tumor Management. Frontiers in oncology 20 33763373
2024 UCP2-SIRT3 Signaling Relieved Hyperglycemia-Induced Oxidative Stress and Senescence in Diabetic Retinopathy. Investigative ophthalmology & visual science 19 38175638
2015 UCP2 knockout suppresses mouse skin carcinogenesis. Cancer prevention research (Philadelphia, Pa.) 19 25784177
2023 CircUCP2 promotes the tumor progression of non-small cell lung cancer through the miR-149/UCP2 pathway. Oncology research 18 37744277
2022 Microglial FABP4-UCP2 Axis Modulates Neuroinflammation and Cognitive Decline in Obese Mice. International journal of molecular sciences 18 35457171
2021 PP2 Ameliorates Renal Fibrosis by Regulating the NF-κB/COX-2 and PPARγ/UCP2 Pathway in Diabetic Mice. Oxidative medicine and cellular longevity 18 34580604
2022 UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling. Frontiers in immunology 17 36275699
2005 Recruitment of mitochondrial uncoupling protein UCP2 after lipopolysaccharide induction. The international journal of biochemistry & cell biology 17 15694840
2023 Variability in oxidative stress-related genes (SOD2, CAT, GPX1, GSTP1, NOS3, NFE2L2, and UCP2) and susceptibility to migraine clinical phenotypes and features. Frontiers in neurology 16 36698892
2020 Brain Overexpression of Uncoupling Protein-2 (UCP2) Delays Renal Damage and Stroke Occurrence in Stroke-Prone Spontaneously Hypertensive Rats. International journal of molecular sciences 16 32560241
2015 Expression of UCP2 in Wistar rats varies according to age and the severity of obesity. Journal of physiology and biochemistry 16 26621256
2014 Hippocampal UCP2 is essential for cognition and resistance to anxiety but not required for the benefits of exercise. Neuroscience 16 25003714
2025 The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injury. Redox biology 15 39874927
2024 UCP2 promotes NSCLC proliferation and glycolysis via the mTOR/HIF-1α signaling. Cancer medicine 15 38217303
2019 UCP2 Overexpression Redirects Glucose into Anabolic Metabolic Pathways. Proteomics 15 30556651
1999 Uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) expression in adipose tissue and skeletal muscle in humans. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 15 10454128
2020 Role and mechanism of FLNa and UCP2 in the development of cervical cancer. Oncology reports 14 33125133
2018 Expression of UCP2 is associated with sensitivity to platinum-based chemotherapy for ovarian serous carcinoma. Oncology letters 14 29928365
2012 An association between -866G/A polymorphism in the promoter of UCP2 and obesity: a meta-analysis. Gene 14 23147265
2011 UCP2 mRNA expression is dependent on glucose metabolism in pancreatic islets. Biochemical and biophysical research communications 14 22177951
2025 UCP2 inhibition eliminates pancreatic β cell autoinflammation in T2DM with islet-mitochondrial sequential targeting nanomedicines. Nature communications 13 40707441
2022 Impact of UCP2 depletion on heat stroke-induced mitochondrial function in human umbilical vein endothelial cells. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 13 35129048

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