Affinage

UCP2

Dicarboxylate carrier SLC25A8 · UniProt P55851

Length
309 aa
Mass
33.2 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UCP2 is a mitochondrial inner membrane protein that governs cellular metabolic routing, mitochondrial ROS production, and downstream signaling across diverse cell types including pancreatic islet cells, macrophages, neurons, endothelial cells, and cancer cells. Reconstitution in lipid vesicles established that UCP2 functions as a C4 metabolite transporter, catalyzing exchange of malate, oxaloacetate, and aspartate for phosphate, thereby limiting mitochondrial glucose oxidation and enabling glutaminolysis and cytosolic NADPH generation (PMID:24395786, PMID:33230296); its proton conductance is activated by fatty acids and retinoids and inhibited by nucleotides and glutathionylation (PMID:10545094, PMID:23069211). UCP2 transcription is repressed by SIRT1 in pancreatic beta cells and induced by KLF2 under shear stress in endothelial cells, while translation is restrained by a 5′-UTR upstream open reading frame and modulated by hnRNPK binding to its 3′ UTR (PMID:16366736, PMID:35899624, PMID:16845607, PMID:15485813). Through its control of mitochondrial ROS, UCP2 regulates AMPK–FoxO1 and HIF-1α signaling, macrophage inflammatory activation, microglial synapse elimination, pancreatic alpha-cell glucagon secretion, stem-cell metabolic transitions, and susceptibility to tumorigenesis (PMID:35899624, PMID:18006654, PMID:33879866, PMID:23434936, PMID:22085932, PMID:31461648).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 High

    Establishing that UCP2 possesses regulatable proton transport activity resolved whether this UCP1 homolog was itself a functional transporter; retinoids were identified as novel activators and nucleotides as inhibitors, defining UCP2's pharmacological profile.

    Evidence Proton transport assay in yeast mitochondria expressing recombinant UCP2, compared with UCP1 and UCP3

    PMID:10545094

    Open questions at the time
    • Whether retinoid activation is physiologically relevant in vivo remained untested
    • Molecular mechanism of retinoid-mediated activation unresolved
    • Transport substrate identity beyond protons was unknown
  2. 2004 Medium

    Identifying translational control mechanisms for UCP2 explained how UCP2 protein levels can be rapidly tuned independently of mRNA: a 5′-UTR uORF suppresses translation, and hnRNPK binding to the 3′ UTR promotes translation on polysome-coated mitochondria.

    Evidence Reporter constructs with uORF mutations plus in vitro translation; yeast three-hybrid identification of hnRNPK, polysome fractionation, Western blot quantification

    PMID:15485813 PMID:16845607

    Open questions at the time
    • Physiological signals that relieve uORF-mediated repression were unidentified
    • Whether hnRNPK-dependent regulation operates in non-insulin-responsive cells was unknown
    • Structural basis of uORF-ribosome interaction not determined
  3. 2005 High

    Demonstrating that SIRT1 directly represses UCP2 transcription in beta cells linked nutrient sensing to mitochondrial uncoupling and insulin secretion, establishing UCP2 as a physiological brake on glucose-stimulated insulin secretion.

    Evidence ChIP showing SIRT1 binding to UCP2 promoter, siRNA rescue of insulin secretion in SIRT1-deficient cells, SIRT1 knockout mice

    PMID:16366736

    Open questions at the time
    • Whether SIRT1-UCP2 axis operates in non-beta-cell contexts was unclear
    • Identity of histone marks modified by SIRT1 at the UCP2 locus not characterized
  4. 2007 High

    UCP2 knockout studies in macrophages and islet alpha cells established that UCP2 controls cell-type-specific functions through ROS modulation: UCP2 loss increases macrophage inflammatory cytokine production via MAPK and impairs alpha-cell glucagon secretion by disrupting stimulus-secretion coupling.

    Evidence UCP2 KO mice with macrophage cytokine/NO assays, insulitis scoring; alpha-cell ATP/O ratios, glucagon secretion, mitochondrial membrane potential; conditional alpha-cell KO with ROS rescue

    PMID:18006654 PMID:18701716 PMID:23434936

    Open questions at the time
    • Whether ROS species mediating effects are superoxide vs. H2O2 was not distinguished
    • Direct ROS targets in alpha-cell secretory machinery unidentified
  5. 2009 High

    Showing that ghrelin-mediated neuroprotection of dopamine neurons requires UCP2 established UCP2 as a downstream effector of neuropeptide signaling in the CNS, linking mitochondrial uncoupling to neuronal survival.

    Evidence Genetic epistasis using GHSR KO mice with selective catecholaminergic reactivation, MPTP neurotoxin model, UCP2-dependent mitochondrial respiration and ROS measurements

    PMID:19906954

    Open questions at the time
    • Whether UCP2 induction by ghrelin is transcriptional or translational was unclear
    • Applicability to human neurodegenerative disease not tested
  6. 2011 High

    Demonstrating that UCP2 prevents mitochondrial glucose oxidation in stem cells and is required for the glycolysis-to-OXPHOS metabolic transition during differentiation revealed UCP2 as a metabolic gatekeeper of cell fate decisions.

    Evidence siRNA knockdown and ectopic overexpression in human pluripotent stem cells, oxygen consumption and metabolic flux assays, differentiation assays

    PMID:22085932

    Open questions at the time
    • Mechanism by which UCP2 is downregulated during differentiation not established
    • Whether substrate shunting or proton leak drives the stem cell effect was unresolved
  7. 2012 Medium

    Post-translational regulation of UCP2 by glutathionylation was shown to deactivate proton leak, establishing redox-sensitive control of UCP2 activity with implications for chemoresistance in leukemia cells.

    Evidence Diamide-induced glutathionylation with proton leak respiration assay and UCP2 knockdown in drug-resistant leukemia cells

    PMID:23069211

    Open questions at the time
    • Specific cysteine residues targeted by glutathionylation not mapped
    • Whether glutathionylation also regulates the metabolite transport function was untested
    • No independent replication in other cell types
  8. 2014 High

    The landmark reconstitution of UCP2 in lipid vesicles redefined its primary molecular function: UCP2 is a C4 metabolite/phosphate exchanger rather than a protonophore, explaining its ability to limit glucose oxidation by exporting oxaloacetate, malate, and aspartate from the mitochondrial matrix.

    Evidence Direct transport assay of reconstituted UCP2 in lipid vesicles; metabolomics and bioenergetic validation in UCP2-silenced HepG2 cells

    PMID:24395786

    Open questions at the time
    • Structural basis for C4 substrate selectivity unknown
    • How proton leak and metabolite transport activities are related mechanistically was unresolved
    • In vivo confirmation of transport specificity lacking
  9. 2017 High

    Multiple studies established UCP2 as a signaling hub linking metabolic substrate routing to downstream kinase pathways: UCP2 modulates FABP4-dependent NLRP3 inflammasome activation in macrophages, ROS-AKT signaling in pancreas development, and AKT-PFKFB2 glycolytic flux in skin cells.

    Evidence FABP4 KO with UCP2 siRNA rescue and inflammasome assays; Ucp2 KO mice with pancreas morphometry and NAC rescue; UCP2 overexpression with AKT/PFKFB2 pathway inhibitor experiments

    PMID:27795298 PMID:29079704 PMID:29221144

    Open questions at the time
    • Whether ROS-AKT and FABP4-UCP2 axes converge on common effectors was unclear
    • Relative contributions of metabolite transport vs. uncoupling to these signaling effects not dissected
  10. 2019 High

    Cell-type-specific conditional knockouts revealed UCP2's roles in microglial biology: UCP2 mediates HFD-induced mitochondrial dynamic changes and hypothalamic inflammation controlling energy balance, and regulates microglial synapse phagocytosis in hippocampus affecting anxiety behavior.

    Evidence Conditional microglial Ucp2 KO with mitochondrial dynamics imaging, POMC neuron activation analysis, synapse phagocytosis confocal imaging, electrophysiology, and behavioral testing

    PMID:31495690 PMID:33879866

    Open questions at the time
    • Molecular link between UCP2-dependent ROS and phagocytic machinery not identified
    • Whether UCP2's metabolite transport or uncoupling function drives microglial effects is unknown
  11. 2020 High

    UCP2's C4 metabolite transport function was validated in cancer metabolism: UCP2-mediated aspartate efflux fuels cytosolic NADPH production via glutaminolysis in KRAS-mutant pancreatic cancer, and UCP2 loss increases colon tumorigenesis by depleting NADPH and promoting phospholipid synthesis.

    Evidence UCP2 siRNA in KRAS-mutant PDAC cells with metabolic flux, NADPH/NADP+ ratio, xenograft models; UCP2 KO in AOM/DSS and ApcMin/+ colon cancer models with metabolomics

    PMID:31461648 PMID:33230296

    Open questions at the time
    • Whether UCP2 transport activity is druggable in cancer contexts is untested
    • Tissue-specific opposing roles (tumor-promoting vs. tumor-suppressive) not mechanistically reconciled
  12. 2022 High

    Identification of KLF2 as a shear-stress-responsive transcription factor that directly activates UCP2 in endothelial cells connected UCP2 to vascular mechanotransduction; UCP2 suppresses endothelial inflammation through AMPK-FoxO1 signaling and protects against atherosclerosis.

    Evidence ChIP for KLF2 binding to UCP2 promoter, EC-specific Ucp2 KO and AAV overexpression in vivo, RNA-seq, AMPK/FoxO1 pathway analysis

    PMID:35899624

    Open questions at the time
    • How UCP2 activates AMPK—through metabolite transport, ROS, or AMP/ATP ratio—is not resolved
    • Whether other shear-responsive transcription factors co-regulate UCP2 is unknown
  13. 2022 Medium

    UCP2 was shown to act as a metabolic oxygen sensor in cardiomyocytes, controlling acetyl-CoA levels and histone acetylation under hypoxia, linking UCP2's metabolite transport to epigenetic regulation of cell cycle activity.

    Evidence UCP2 global KO mice under hypoxia with acetyl-CoA measurement, histone acetylation assay, DNA damage markers, cardiomyocyte cell cycle analysis

    PMID:35771638

    Open questions at the time
    • Mechanism by which UCP2 senses oxygen not determined
    • Whether acetyl-CoA changes reflect altered transport or altered TCA flux is unclear
    • Not confirmed with conditional cardiomyocyte-specific KO

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified structural and biophysical model reconciling UCP2's dual activities—C4 metabolite transport and regulatable proton conductance—is lacking, and the relative contribution of each activity to UCP2's diverse cell-type-specific phenotypes remains unresolved.
  • No high-resolution structure of UCP2 in a transport-competent state with bound substrate
  • Cell-type-specific conditional studies have not systematically separated metabolite transport from uncoupling
  • Druggability of UCP2 transport function is unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140104 molecular carrier activity 2
Localization
GO:0005739 mitochondrion 5
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2
Partners
FABP4HNRNPKKLF2SIRT1SIRT3

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Retinoids (retinoic acid) activate proton transport by UCP2 in a pH-dependent manner, demonstrated using yeast mitochondria expressing UCP2 by genetic manipulation; UCP2 proton conductance is positively regulated by retinoids and negatively regulated by nucleotides, analogous to UCP1 but with distinct pharmacology. In vitro proton transport assay in yeast mitochondria expressing recombinant UCP2; comparison with UCP1 and UCP3 The EMBO journal High 10545094
2005 SIRT1 represses UCP2 transcription by binding directly to the UCP2 promoter in pancreatic beta cells; reduced SIRT1 leads to elevated UCP2, blunted ATP production after glucose stimulation, and impaired insulin secretion; UCP2 knockdown rescues insulin secretion in SIRT1-deficient cells. ChIP (SIRT1 binding to UCP2 promoter), siRNA knockdown of SIRT1 and UCP2, glucose-stimulated insulin secretion assay, SIRT1 knockout mice PLoS biology High 16366736
2006 UCP2 mRNA translation is controlled by an upstream open reading frame (uORF) in its 5' UTR encoding a 36-amino-acid peptide; the 3' region of the uORF is the major determinant of translational inhibition, and silent single-base substitutions in this region significantly alter UCP2 translation. Reporter constructs with uORF mutations, in vitro translation assays Cellular and molecular life sciences : CMLS Medium 16845607
2004 hnRNPK (heterogeneous nuclear ribonucleoprotein K) binds to the 3' UTR of ucp2 mRNA and associates with polysome-coated mitochondria; hnRNPK overexpression augments insulin-induced mitochondrial UCP2 protein levels without changing mRNA levels, indicating translational regulation. Yeast three-hybrid screen, co-immunoprecipitation, polysome fractionation, Western blot The Journal of biological chemistry Medium 15485813
2011 UCP2 prevents mitochondrial glucose oxidation in human pluripotent stem cells (hPSCs) and facilitates glycolysis via a substrate shunting mechanism; ectopic UCP2 expression perturbs the metabolic transition during differentiation and impairs differentiation potential. siRNA knockdown and ectopic overexpression of UCP2, oxygen consumption measurements, metabolic flux assays, differentiation assays The EMBO journal High 22085932
2014 UCP2 functions as a mitochondrial metabolite transporter: when reconstituted in lipid vesicles, UCP2 catalyzes exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton; by exporting C4 compounds out of mitochondria, UCP2 limits glucose oxidation and enhances glutaminolysis. Reconstitution of UCP2 in lipid vesicles with direct transport assay; metabolomics of siUCP2-HepG2 cells; mitochondrial membrane potential and ATP:ADP measurements Proceedings of the National Academy of Sciences of the United States of America High 24395786
2020 UCP2 catalyzes aspartate efflux from mitochondria in KRAS-mutant pancreatic cancer cells, connecting mitochondrial glutamine metabolism to cytosolic NADPH production; UCP2 silencing decreases glutaminolysis, lowers NADPH/NADP+ and glutathione ratios, increases ROS, and suppresses KRASmut PDAC cell growth in vitro and in vivo. UCP2 siRNA knockdown, metabolic flux assays, NADPH/NADP+ measurement, ROS detection, xenograft tumor models Nature metabolism High 33230296
2012 Glutathionylation of UCP2 deactivates proton leak; chemical induction of glutathionylation (diamide) selectively inhibits proton leak through UCP2 in drug-resistant leukemia (Mx2) cells, disabling chemoresistance; UCP2 knockdown reduces state 4 (proton leak-dependent) respiration by ~62%. Diamide-induced glutathionylation, proton leak respiration assay, UCP2 knockdown, cell viability with chemotherapeutics Biochimica et biophysica acta Medium 23069211
2008 UCP2 is expressed at significantly higher levels in pancreatic alpha-cells than beta-cells; reducing UCP2 activity in alpha-cells increases mitochondrial membrane potential and ATP synthesis efficiency, leads to reduced glucagon secretion at low glucose, and increases alpha-cell sensitivity to death stimuli. UCP2−/− mice, mitochondrial membrane potential measurement, ATP/O ratio, glucagon secretion assays, cell death assays Proceedings of the National Academy of Sciences of the United States of America High 18701716
2013 Alpha-cell-specific UCP2 deletion impairs glucagon secretion in response to hypoglycemia; UCP2-deleted alpha-cells accumulate intracellular ROS due to enhanced mitochondrial coupling, which directly perturbs stimulus-secretion coupling; exogenous ROS application mimics UCP2 deletion effects on glucagon secretion. Alpha-cell-specific UCP2 knockout mice, ROS measurement, glucagon secretion assay, genipin pharmacological inhibition of UCP2, human islet studies Diabetes High 23434936
2007 UCP2 controls macrophage activation by modulating mitochondrial ROS production and MAPK signaling; UCP2-deficient macrophages show increased IL-1β and nitric oxide production, leading to accelerated autoimmune diabetes in a streptozotocin model. UCP2 knockout mice, macrophage cytokine assays, NO measurement, insulitis scoring Proceedings of the National Academy of Sciences of the United States of America High 18006654
2009 Ghrelin-induced neuroprotection of nigrostriatal dopamine neurons is dependent on UCP2-mediated alterations in mitochondrial respiration, ROS production, and biogenesis; ghrelin receptor (GHSR) activation in substantia nigra requires UCP2 for its mitochondrial redox mechanism of protection. Ghrelin/GHSR knockout mice, MPTP neurotoxin model, selective GHSR reactivation in catecholaminergic neurons, mitochondrial respiration and ROS assays, UCP2-dependent rescue experiments The Journal of neuroscience High 19906954
2019 Microglial UCP2 mediates HFD-induced changes in mitochondrial dynamics and microglia activation; selective microglial deletion of Ucp2 prevents mitochondrial dynamic changes, microglia activation, and hypothalamic inflammation, protecting mice from diet-induced obesity with decreased feeding and increased energy expenditure. Conditional microglial Ucp2 knockout, mitochondrial dynamics imaging, hypothalamic inflammation markers, synaptic input analysis, POMC neuron activation Cell metabolism High 31495690
2021 Microglial UCP2 regulates phasic elimination of spine synapses in ventral hippocampus; conditional Ucp2 ablation from microglia impairs synapse phagocytosis, causes ROS accumulation and lysosome-lipid droplet complex formation, resulting in hippocampal circuit dysfunction and altered anxiety-like behavior. Conditional microglial Ucp2 KO, confocal imaging of microglia-synapse contacts, ROS assay, electrophysiology, behavioral testing Molecular psychiatry High 33879866
2008 UCP2 upregulation in NASH liver induces mitochondrial proton leak, measured directly as increased proton conductance in isolated mitochondria; this correlates with increased H2O2 production and decreased ATP content, reducing the liver's ability to respond to acute energy demands such as ischemia-reperfusion. Isolated mitochondria proton leak measurement, H2O2 synthesis assay, GSH/GSSG ratio, ATP homeostasis in NASH rat model and human biopsy samples Gut Medium 18308829
2017 UCP2 controls mitochondrial ROS and MAPK signaling in macrophages through the FABP4-UCP2 axis; FABP4 deletion elevates intracellular free fatty acids and increases UCP2 expression, reducing ER stress, NLRP3 inflammasome activation, and IL-1β secretion; these effects are reversed by UCP2 silencing. FABP4/aP2 knockout and pharmacological inhibition, UCP2 siRNA, inflammasome activation assays, mitochondrial protein oxidation proteomics Molecular and cellular biology High 27795298
2014 UCP2 overexpression in cancer cells restores oxidative phosphorylation balance (reversing Warburg effect) through substrate routing (not membrane potential uncoupling), activates AMPK signaling, and downregulates HIF expression, repressing malignant phenotypes. UCP2 overexpression in cancer cell lines, Seahorse metabolic flux analysis, AMPK and HIF protein measurement, tumorigenesis assays Cancer research Medium 24853548
2022 In endothelial cells, KLF2 directly binds the UCP2 promoter to upregulate its transcription in response to unidirectional shear stress; UCP2 suppresses endothelial inflammation through AMPK-mediated inhibition of FoxO1; EC-specific Ucp2 deletion promotes atherosclerosis, while AAV-mediated overexpression inhibits it. ChIP (KLF2 binding to UCP2 promoter), shear stress simulation, EC-specific Ucp2 KO mice, AAV-mediated overexpression, RNA-seq, AMPK/FoxO1 pathway analysis Circulation research High 35899624
2005 UCP2 is recruited to hepatocyte mitochondria after LPS challenge; LPS increases UCP2 protein 3-fold (quantified by 3H-GTP binding sites), reduces mitochondrial membrane potential, and increases H2O2 production reversed by GDP (UCP2 inhibitor), indicating functional UCP2-mediated uncoupling in hepatocytes during infection. 3H-GTP binding assay for UCP2 protein quantification, mitochondrial membrane potential (JC-1), H2O2 assay with GDP inhibition, real-time RT-PCR The international journal of biochemistry & cell biology Medium 15694840
2012 UCP2 inhibition triggers ROS-dependent nuclear translocation of GAPDH and autophagic cell death in pancreatic adenocarcinoma cells; UCP2 overexpression reduces basal autophagy, establishing an anti-autophagic role for UCP2 through ROS control. Genipin pharmacological inhibition and siRNA knockdown of UCP2, ROS measurement, GAPDH nuclear translocation assay, autophagosome formation, LC3-II Western blot, UCP2 overexpression Biochimica et biophysica acta Medium 23124112
2017 UCP2 controls pancreas development through a ROS-AKT signaling pathway; Ucp2 knockout mice show increased PDX1+ progenitor cells and expanded alpha- and beta-cell mass, associated with increased NRF2 nuclear translocation and AKT phosphorylation; N-acetylcysteine administration rescued the pancreatic developmental phenotype. Ucp2 knockout mice, pancreas morphometry, ROS measurement, NRF2 nuclear translocation assay, pAKT Western blot, antioxidant rescue experiment Diabetes High 29079704
2019 UCP2 deficiency increases colon tumorigenesis by promoting phospholipid synthesis and depleting NADPH for antioxidant defenses; UCP2 loss alters glycolytic pathways and increases oxidized glutathione levels, rendering colon cells more prone to malignant transformation. UCP2 KO in AOM/DSS and ApcMin/+ mouse cancer models, metabolomics (NADPH, glutathione oxidation, phospholipid), tumor histopathology Cell reports High 31461648
2022 UCP2 acts as a metabolic oxygen sensor in cardiomyocytes; under moderate hypoxia, UCP2 increases acetyl-CoA levels and histone acetylation, promoting cardiomyocyte cell cycle activity; UCP2 knockout under hypoxia reduces cardiomyocyte cell cycle activity, increases DNA damage and fibrosis. UCP2 global KO mice under hypoxia, acetyl-CoA measurement, histone acetylation assay, chromatin modifier analysis, DNA damage markers, cardiomyocyte cell cycle analysis JCI insight Medium 35771638
2002 UCP2 is expressed in neurons of subcortical brain regions and is rapidly induced after brain lesions with an inverse relationship to caspase-3 activation; overexpression of UCP2 in transgenic mice reduces apoptotic signaling after injury. UCP2 transgenic overexpression mice, brain lesion model, caspase-3 immunohistochemistry, in situ hybridization Biochemical pharmacology Medium 12147286
2000 UCP2 mRNA and protein are expressed in specific hypothalamic nuclei (paraventricular, supraoptic, suprachiasmatic, arcuate) and pituitary of nonhuman primates; UCP2 is co-expressed with neuropeptide Y, CRH, oxytocin, and vasopressin in neurons, and with POMC cells in pituitary. In situ hybridization, immunocytochemistry, co-localization with neuropeptide markers in primate brain sections Endocrinology Medium 11089557
2002 UCP2 modulates sensitivity to ethanol and pain/temperature sensation in the CNS; UCP2 overexpressing mice show decreased ethanol sensitivity while UCP2 knockouts show increased sensitivity; UCP2 expression is inversely correlated with ethanol-induced impairment of pain and temperature sensation. UCP2 transgenic overexpression and knockout mice, acute ethanol challenge, behavioral assays for pain and temperature sensation Biochemical pharmacology Medium 12147287
1999 UCP2 expression in human PAZ6 adipocytes is rapidly upregulated by thiazolidinediones (PPARγ agonists), but the increase parallels general adipocyte differentiation markers, suggesting transcriptional regulation through PPARγ-mediated differentiation rather than a UCP2-specific effect. RT-PCR of UCP2 mRNA in human adipocytes after thiazolidinedione treatment, time-course experiment Diabetologia Low 10333043
2024 UCP2 overexpression protects retinal endothelial cells from hyperglycemia-induced oxidative stress and senescence through a UCP2-NAD+-SIRT3 axis; UCP2 overexpression attenuates NAD+ downregulation under high glucose, promotes SIRT3 expression and activity, and SIRT3 inhibition abolishes UCP2-mediated protection. Adenovirus-mediated UCP2 overexpression and knockdown, ROS flow cytometry, SA-β-gal senescence assay, NAD+ measurement, SIRT3 inhibitor (3-TYP) rescue experiment Investigative ophthalmology & visual science Medium 38175638
2022 UCP2 silencing in T-ALL leukemia cells decreases cell proliferation and alters mitochondrial respiration; UCP2 function in malate export enables TCA cycle to provide lipid building blocks for cell growth; glutamine metabolism controls UCP2 expression in T-ALL. UCP2 siRNA knockdown in T-ALL cell lines, metabolic flux analysis (NMR), Seahorse respirometry, lipid synthesis measurement Frontiers in immunology Medium 36275699
2020 UCP2 regulates tubulointerstitial fibrosis by inducing HIF-1α stabilization through mitochondrial respiration and tissue hypoxia; UCP2-deficient mice show reduced renal fibrosis after ischemia-reperfusion; HIF-1α inhibition suppresses lipid and ECM accumulation by restoring PPARα and CPT1α. UCP2-deficient mice, I/R kidney model, HIF-1α siRNA, lipid deposition measurement, ECM marker Western blot, mitochondrial respiration assay Cell death & disease Medium 31932578
2017 UCP2 overexpression in skin cells (JB6 model) activates PFKFB2 through AKT signaling, elevating fructose 2,6-bisphosphate and glycolytic flux; PFKFB2 inhibition suppresses UCP2-mediated transformation and restores mitochondrial respiration. UCP2 overexpression in JB6 cells, PFKFB2 knockdown, glucose uptake, lactate production, PFK-1 activity, AKT pathway inhibitor experiments Oncotarget Medium 29221144

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
2005 Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS biology 600 16366736
2011 UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. The EMBO journal 409 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 336 24395786
1998 Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima indians. Human molecular genetics 251 9700198
2009 Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience 232 19906954
2019 Matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway. Acta pharmaceutica Sinica. B 223 31384530
2003 The 'novel' 'uncoupling' proteins UCP2 and UCP3: what do they really do? Pros and cons for suggested functions. Experimental physiology 194 12525856
2019 Microglial UCP2 Mediates Inflammation and Obesity Induced by High-Fat Feeding. Cell metabolism 193 31495690
2011 Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism. Trends in molecular medicine 179 21917523
2008 Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury. Gut 175 18308829
1999 Retinoids activate proton transport by the uncoupling proteins UCP1 and UCP2. The EMBO journal 172 10545094
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 143 23807210
2018 A Ketogenic Diet Improves Mitochondrial Biogenesis and Bioenergetics via the PGC1α-SIRT3-UCP2 Axis. Neurochemical research 127 30027365
2009 UCP2, not a physiologically relevant uncoupler but a glucose sparing switch impacting ROS production and glucose sensing. Biochimica et biophysica acta 114 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 107 33230296
2002 Brain mitochondrial uncoupling protein 2 (UCP2): a protective stress signal in neuronal injury. Biochemical pharmacology 104 12147286
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 81 23124112
2001 T(3) increases mitochondrial ATP production in oxidative muscle despite increased expression of UCP2 and -3. American journal of physiology. Endocrinology and metabolism 80 11287359
2017 FABP4/aP2 Regulates Macrophage Redox Signaling and Inflammasome Activation via Control of UCP2. Molecular and cellular biology 78 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 73 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
2007 Inhibition of UCP2 expression reverses diet-induced diabetes mellitus by effects on both insulin secretion and action. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 73 17209127
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
2019 UCP2 ameliorates mitochondrial dysfunction, inflammation, and oxidative stress in lipopolysaccharide-induced acute kidney injury. International immunopharmacology 69 30952098
2007 Role of uncoupling protein UCP2 in cell-mediated immunity: how macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes. Proceedings of the National Academy of Sciences of the United States of America 65 18006654
2015 Indoxyl sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting the AMPK/UCP2 signaling pathway. Toxicology letters 64 25703824
2008 Overexpression of UCP2 protects thalamic neurons following global ischemia in the mouse. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 64 18301432
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
2022 Endothelial UCP2 Is a Mechanosensitive Suppressor of Atherosclerosis. Circulation research 60 35899624
2017 COL1A1, PRPF40A, and UCP2 correlate with hypoxia markers in non-small cell lung cancer. Journal of cancer research and clinical oncology 57 28258342
2018 Mutant p53 blocks SESN1/AMPK/PGC-1α/UCP2 axis increasing mitochondrial O2-· production in cancer cells. British journal of cancer 56 30318520
2009 Glycine regulates inflammatory markers modifying the energetic balance through PPAR and UCP-2. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 56 19864106
2019 UCP2 gene polymorphisms in obesity and diabetes, and the role of UCP2 in cancer. FEBS letters 55 31330574
2017 Identification of a fatty acid binding protein4-UCP2 axis regulating microglial mediated neuroinflammation. Molecular and cellular neurosciences 54 28214555
2017 Leishmania donovani inhibits inflammasome-dependent macrophage activation by exploiting the negative regulatory proteins A20 and UCP2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 52 28765172
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
2019 UCP2 promotes proliferation and chemoresistance through regulating the NF-κB/β-catenin axis and mitochondrial ROS in gallbladder cancer. Biochemical pharmacology 46 31811866
2006 Translation control of UCP2 synthesis by the upstream open reading frame. Cellular and molecular life sciences : CMLS 46 16845607
2000 Mitochondrial uncoupling protein 2 (UCP2) in the nonhuman primate brain and pituitary. Endocrinology 45 11089557
2021 An interplay between UCP2 and ROS protects cells from high-salt-induced injury through autophagy stimulation. Cell death & disease 44 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 39 31461648
2017 Upregulation of UCP2 in beta-cells confers partial protection against both oxidative stress and glucotoxicity. Redox biology 38 28755631
2012 Glutathionylation of UCP2 sensitizes drug resistant leukemia cells to chemotherapeutics. Biochimica et biophysica acta 38 23069211
2015 UCP2-related mitochondrial pathway participates in oroxylin A-induced apoptosis in human colon cancer cells. Journal of cellular physiology 37 25251374
2018 Effects of resveratrol on regulation on UCP2 and cardiac function in diabetic rats. Journal of physiology and biochemistry 36 30225723
2017 UCP2 overexpression enhanced glycolysis via activation of PFKFB2 during skin cell transformation. Oncotarget 36 29221144
2022 Genipin, an Inhibitor of UCP2 as a Promising New Anticancer Agent: A Review of the Literature. International journal of molecular sciences 35 35628447
2022 UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control. International journal of molecular sciences 35 36499405
2019 UCP2 alleviates tubular epithelial cell apoptosis in lipopolysaccharide-induced acute kidney injury by decreasing ROS production. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 35 31071510
2004 Heterogeneous nuclear ribonucleoprotein K enhances insulin-induced expression of mitochondrial UCP2 protein. The Journal of biological chemistry 33 15485813
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 32 36699054
2019 Upregulation of UCP2 Expression Protects against LPS-Induced Oxidative Stress and Apoptosis in Cardiomyocytes. Oxidative medicine and cellular longevity 31 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
2008 UCP-2 and UCP-3 proteins are differentially regulated in pancreatic beta-cells. PloS one 31 18167556
2023 Exploring a new mechanism between lactate and VSMC calcification: PARP1/POLG/UCP2 signaling pathway and imbalance of mitochondrial homeostasis. Cell death & disease 30 37679327
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
2021 ShenmaYizhi Decoction Improves the Mitochondrial Structure in the Brain and Ameliorates Cognitive Impairment in VCI Rats via the AMPK/UCP2 Signaling Pathway. Neuropsychiatric disease and treatment 28 34168453
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
2021 Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior. Molecular psychiatry 26 33879866
2016 Role of UCP2 in the protective effects of PPARβ/δ activation on lipopolysaccharide-induced endothelial dysfunction. Biochemical pharmacology 26 27179975
2018 Overexpressed UCP2 regulates mitochondrial flashes and reverses lipopolysaccharide-induced cardiomyocytes injury. American journal of translational research 25 29887950
2007 Association of UCP2 and UCP3 gene polymorphisms with serum high-density lipoprotein cholesterol among Korean women. Metabolism: clinical and experimental 25 17512314
2003 Cardiac UCP2 expression and myocardial oxidative metabolism during acute septic shock in the rat. Shock (Augusta, Ga.) 25 12785014
2018 PEDF protects human retinal pigment epithelial cells against oxidative stress via upregulation of UCP2 expression. Molecular medicine reports 24 30431098
2021 Hypoxanthine Induces Muscular ATP Depletion and Fatigue via UCP2. Frontiers in physiology 23 33746782
1999 Regulation of UCP2 and UCP3 by muscle disuse and physical activity in tetraplegic subjects. Diabetologia 23 10440124
2022 UCP2 modulates cardiomyocyte cell cycle activity, acetyl-CoA, and histone acetylation in response to moderate hypoxia. JCI insight 22 35771638
2016 Role of mitochondrial uncoupling protein-2 (UCP2) in higher brain functions, neuronal plasticity and network oscillation. Molecular metabolism 22 27257601
2011 Polymorphisms of the UCP2 gene are associated with body fat distribution and risk of abdominal obesity in Spanish population. European journal of clinical investigation 22 21883184
2021 Activation of UCP2 by anethole trithione suppresses neuroinflammation after intracerebral hemorrhage. Acta pharmacologica Sinica 21 34183754
2020 Fish oil and chicoric acid combination protects better against palmitate-induced lipid accumulation via regulating AMPK-mediated SREBP-1/FAS and PPARα/UCP2 pathways. Archives of physiology and biochemistry 21 32654534
2013 UCP2 and ANT differently modulate proton-leak in brain mitochondria of long-term hyperglycemic and recurrent hypoglycemic rats. Journal of bioenergetics and biomembranes 21 23504111
2003 Lack of association between UCP2 gene polymorphisms and obesity phenotype in Italian Caucasians. Journal of endocrinological investigation 21 14759071
2000 Correlation between pancreatic islet uncoupling protein-2 (UCP2) mRNA concentration and insulin status in rats. International journal of experimental diabetes research 21 11467409
2021 The effects of UCP2 on autophagy through the AMPK signaling pathway in septic cardiomyopathy and the underlying mechanism. Annals of translational medicine 19 33708886
2019 UCP2 regulates cholangiocarcinoma cell plasticity via mitochondria-to-AMPK signals. Biochemical pharmacology 19 31085159
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
2025 Irisin regulates oxidative stress and mitochondrial dysfunction through the UCP2-AMPK pathway in prion diseases. Cell death & disease 17 39900919
2005 Recruitment of mitochondrial uncoupling protein UCP2 after lipopolysaccharide induction. The international journal of biochemistry & cell biology 17 15694840
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
2024 UCP2-SIRT3 Signaling Relieved Hyperglycemia-Induced Oxidative Stress and Senescence in Diabetic Retinopathy. Investigative ophthalmology & visual science 15 38175638
2022 Endothelial Cells Mediated by UCP2 Control the Neurogenic-to-Astrogenic Neural Stem Cells Fate Switch During Brain Development. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 15 35488517
2022 UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling. Frontiers in immunology 15 36275699
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 15 32560241
2012 An association between -866G/A polymorphism in the promoter of UCP2 and obesity: a meta-analysis. Gene 14 23147265