Ucp2 (SLC25A8) encodes mitochondrial uncoupling protein 2, a 309-residue member of the mitochondrial carrier (SLC25) family with six transmembrane helices in three Mito_carr repeats, located in the inner mitochondrial membrane. Despite its name and homology to the thermogenic UCP1, its principal activity (shown for the human and mouse orthologues) is an antiport that exports four-carbon Krebs-cycle intermediates (malate, oxaloacetate, aspartate) from the matrix in exchange for phosphate plus a proton; by draining C4 metabolites it limits oxidation of acetyl-CoA-producing substrates such as glucose, favours glutaminolysis, and lowers the ATP/ADP ratio and mitochondrial ROS production. UCP2 also mediates a fatty-acid-activated, purine-nucleotide-inhibited proton conductance whose physiological weight is debated, and it does not mediate adaptive thermogenesis. In rat INS-1E beta cells UCP2 is a low-abundance protein with a half-life of about 1 h whose level is set by glutamine-dependent translation and glucose; it contributes to proton leak and restrains glucose-stimulated insulin secretion while protecting against oxidative stress. Rat UCP2 is widely expressed (notably spleen, lung, heart, kidney, pancreas, adipocytes and hypothalamus), and its expression responds to nutrients, hormones and oxidative or inflammatory stress.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000266 mitochondrial fission | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mitochondrial fission (orthology from mouse). Reason: Transferred from mouse, where UCP2 is required for glucose-induced DRP1-dependent mitochondrial fission in VMH neurons. A context-specific, indirect role (UCP2 is not part of the fission machinery); kept as non-core. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Required for glucose-induced DRP1-dependent mitochondrial fission and neuron activation in the ventromedial nucleus of the hypothalamus (VMH) |
| GO:0000266 mitochondrial fission | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mitochondrial fission (orthology from mouse). Reason: Transferred from mouse, where UCP2 is required for glucose-induced DRP1-dependent mitochondrial fission in VMH neurons. A context-specific, indirect role (UCP2 is not part of the fission machinery); kept as non-core. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Required for glucose-induced DRP1-dependent mitochondrial fission and neuron activation in the ventromedial nucleus of the hypothalamus (VMH) |
| GO:0000266 mitochondrial fission | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mitochondrial fission (orthology from mouse). Reason: Transferred from mouse, where UCP2 is required for glucose-induced DRP1-dependent mitochondrial fission in VMH neurons. A context-specific, indirect role (UCP2 is not part of the fission machinery); kept as non-core. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Required for glucose-induced DRP1-dependent mitochondrial fission and neuron activation in the ventromedial nucleus of the hypothalamus (VMH) |
| GO:0000303 response to superoxide | IDA PMID:12372827 Superoxide activates mitochondrial uncoupling protein 2 from... | KEEP AS NON CORE | Summary: Response to superoxide. Reason: In isolated rat kidney mitochondria, exogenous or matrix-generated superoxide activated a nucleotide-sensitive proton conductance attributed to UCP2 (Echtay et al. 2002). This is a direct regulatory response of the carrier to superoxide, so the term is reasonable, but the superoxide/alkenal activation model of UCP2 proton leak was later disputed and is peripheral to the C4-dicarboxylate antiport; non-core. Supporting Evidence: PMID:12372827 superoxide activates UCP2 in rat kidney mitochondria from the matrix side of the mitochondrial inner membrane PMID:12372827 Superoxide activates nucleotide-sensitive mitochondrial proton transport through the uncoupling proteins UCP1, UCP2, and UCP3 file:rat/Ucp2/Ucp2-uniprot.txt This activity and its potential regulation by ubiquinones and nucleotides was disputed by later studies, which failed to reproduce the effect on proton conductance under physiological conditions. |
| GO:0000303 response to superoxide | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Response to superoxide (ARBA). Reason: Electronic ARBA rule consistent with the rat IDA row from PMID:12372827 (superoxide activation of UCP2 in kidney mitochondria); kept non-core for the same reasons as that row. Supporting Evidence: PMID:12372827 superoxide activates UCP2 in rat kidney mitochondria from the matrix side of the mitochondrial inner membrane |
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Response to hypoxia. Reason: Ucp2 transcripts rise in rat ventricles after chronic hypobaric hypoxia (IEP), and in human cells overexpressed UCP2 limits hypoxic ROS and apoptosis (source of the orthology rows). A downstream, protective physiological response rather than the molecular role; non-core. Supporting Evidence: PMID:17704287 COXIV and UCP2 gene expression were increased in the left ventricle in response to chronic hypobaric hypoxia. file:rat/Ucp2/Ucp2-uniprot.txt 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 |
| GO:0001666 response to hypoxia | IEP PMID:17704287 Genomic modulation of mitochondrial respiratory genes in the... | KEEP AS NON CORE | Summary: Response to hypoxia. Reason: Ucp2 transcripts rise in rat ventricles after chronic hypobaric hypoxia (IEP), and in human cells overexpressed UCP2 limits hypoxic ROS and apoptosis (source of the orthology rows). A downstream, protective physiological response rather than the molecular role; non-core. Supporting Evidence: PMID:17704287 COXIV and UCP2 gene expression were increased in the left ventricle in response to chronic hypobaric hypoxia. file:rat/Ucp2/Ucp2-uniprot.txt 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 |
| GO:0001666 response to hypoxia | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Response to hypoxia. Reason: Ucp2 transcripts rise in rat ventricles after chronic hypobaric hypoxia (IEP), and in human cells overexpressed UCP2 limits hypoxic ROS and apoptosis (source of the orthology rows). A downstream, protective physiological response rather than the molecular role; non-core. Supporting Evidence: PMID:17704287 COXIV and UCP2 gene expression were increased in the left ventricle in response to chronic hypobaric hypoxia. file:rat/Ucp2/Ucp2-uniprot.txt 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 |
| GO:0005324 long-chain fatty acid transmembrane transporter activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Long-chain fatty acid transmembrane transporter activity (orthology). Reason: Fatty-acid anion flipping is the proposed mechanism behind fatty-acid-activated proton conductance of UCPs, supported for mouse UCP2. Secondary to the C4-dicarboxylate/phosphate antiport; non-core. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt The proton currents are most likely associated with fatty acid flipping across the inner membrane of mitochondria |
| GO:0005324 long-chain fatty acid transmembrane transporter activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Long-chain fatty acid transmembrane transporter activity (orthology). Reason: Fatty-acid anion flipping is the proposed mechanism behind fatty-acid-activated proton conductance of UCPs, supported for mouse UCP2. Secondary to the C4-dicarboxylate/phosphate antiport; non-core. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt The proton currents are most likely associated with fatty acid flipping across the inner membrane of mitochondria |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | MODIFY | Summary: Mitochondrion. Reason: Correct but less specific than the established location: UCP2 is a multi-pass SLC25 carrier of the inner mitochondrial membrane, a term this gene already carries (GO:0005743, accepted here). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P55851 SUPPORTS TRANSFER Orthologous UCP2; transfer is sound, but the term is less specific than warranted. Proposed replacements: mitochondrial inner membrane Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Mitochondrion inner membrane |
| GO:0005739 mitochondrion | ISO GO_REF:0000121 | MODIFY | Summary: Mitochondrion. Reason: Correct but less specific than the established location: UCP2 is a multi-pass SLC25 carrier of the inner mitochondrial membrane, a term this gene already carries (GO:0005743, accepted here). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P55851 SUPPORTS TRANSFER Orthologous UCP2; transfer is sound, but the term is less specific than warranted. Proposed replacements: mitochondrial inner membrane Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial inner membrane. Reason: UCP2 is a six-transmembrane mitochondrial carrier (three Mito_carr repeats) of the inner membrane, where it exchanges C4 metabolites for phosphate. Rat UCP2 was detected in mitochondria from rat spleen, kidney and pancreas (PMID:18692019). Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Mitochondrion inner membrane file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Mitochondrial inner membrane. Reason: UCP2 is a six-transmembrane mitochondrial carrier (three Mito_carr repeats) of the inner membrane, where it exchanges C4 metabolites for phosphate. Rat UCP2 was detected in mitochondria from rat spleen, kidney and pancreas (PMID:18692019). Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Mitochondrion inner membrane file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0005743 mitochondrial inner membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Mitochondrial inner membrane. Reason: UCP2 is a six-transmembrane mitochondrial carrier (three Mito_carr repeats) of the inner membrane, where it exchanges C4 metabolites for phosphate. Rat UCP2 was detected in mitochondria from rat spleen, kidney and pancreas (PMID:18692019). Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Mitochondrion inner membrane file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial inner membrane. Reason: UCP2 is a six-transmembrane mitochondrial carrier (three Mito_carr repeats) of the inner membrane, where it exchanges C4 metabolites for phosphate. Rat UCP2 was detected in mitochondria from rat spleen, kidney and pancreas (PMID:18692019). Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Mitochondrion inner membrane file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0006096 glycolysis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Glycolysis. Reason: UCP2 influences the balance between glycolysis and mitochondrial glucose oxidation by exporting C4 metabolites (silencing data in human HepG2 cells), but it performs no glycolytic step; indirect. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P55851 SUPPORTS TRANSFER Human UCP2 silencing alters glucose/glutamine oxidation; the orthology transfer is sound but the term names a metabolic pathway UCP2 regulates rather than performs. Supporting Evidence: PMID:24395786 by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. |
| GO:0006096 glycolysis | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Glycolysis. Reason: UCP2 influences the balance between glycolysis and mitochondrial glucose oxidation by exporting C4 metabolites (silencing data in human HepG2 cells), but it performs no glycolytic step; indirect. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P55851 SUPPORTS TRANSFER Human UCP2 silencing alters glucose/glutamine oxidation; the orthology transfer is sound but the term names a metabolic pathway UCP2 regulates rather than performs. Supporting Evidence: PMID:24395786 by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. |
| GO:0006096 glycolysis | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Glycolysis. Reason: UCP2 influences the balance between glycolysis and mitochondrial glucose oxidation by exporting C4 metabolites (silencing data in human HepG2 cells), but it performs no glycolytic step; indirect. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P55851 SUPPORTS TRANSFER Human UCP2 silencing alters glucose/glutamine oxidation; the orthology transfer is sound but the term names a metabolic pathway UCP2 regulates rather than performs. Supporting Evidence: PMID:24395786 by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. |
| GO:0006541 L-glutamine metabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: L-glutamine metabolic process. Reason: UCP2 export of C4 metabolites enhances glutaminolysis, but UCP2 does not catalyse glutamine metabolism; indirect involvement. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P55851 SUPPORTS TRANSFER Human UCP2 silencing alters glucose/glutamine oxidation; the orthology transfer is sound but the term names a metabolic pathway UCP2 regulates rather than performs. Supporting Evidence: PMID:24395786 by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. |
| GO:0006541 L-glutamine metabolic process | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: L-glutamine metabolic process. Reason: UCP2 export of C4 metabolites enhances glutaminolysis, but UCP2 does not catalyse glutamine metabolism; indirect involvement. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P55851 SUPPORTS TRANSFER Human UCP2 silencing alters glucose/glutamine oxidation; the orthology transfer is sound but the term names a metabolic pathway UCP2 regulates rather than performs. Supporting Evidence: PMID:24395786 by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. |
| GO:0006541 L-glutamine metabolic process | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: L-glutamine metabolic process. Reason: UCP2 export of C4 metabolites enhances glutaminolysis, but UCP2 does not catalyse glutamine metabolism; indirect involvement. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P55851 SUPPORTS TRANSFER Human UCP2 silencing alters glucose/glutamine oxidation; the orthology transfer is sound but the term names a metabolic pathway UCP2 regulates rather than performs. Supporting Evidence: PMID:24395786 by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. |
| GO:0006839 mitochondrial transport | IDA PMID:12372827 Superoxide activates mitochondrial uncoupling protein 2 from... | TOO GENERAL | Summary: Mitochondrial transport (IDA, rat kidney mitochondria). Reason: The IDA measured nucleotide-sensitive, superoxide-activated proton transport across the inner membrane of rat kidney mitochondria. True but uninformative: GO:1990542 mitochondrial transmembrane transport, accepted in this review, already entails it. Supporting Evidence: PMID:12372827 superoxide activates UCP2 in rat kidney mitochondria from the matrix side of the mitochondrial inner membrane |
| GO:0008271 secondary active sulfate transmembrane transporter activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Secondary active sulfate transmembrane transporter activity (orthology). Reason: Reconstituted human UCP2 exchanges sulfate for phosphate in vitro (Rhea:73391); a substrate-range property of the carrier rather than its physiological role. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. |
| GO:0008271 secondary active sulfate transmembrane transporter activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Secondary active sulfate transmembrane transporter activity (orthology). Reason: Reconstituted human UCP2 exchanges sulfate for phosphate in vitro (Rhea:73391); a substrate-range property of the carrier rather than its physiological role. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. |
| GO:0008271 secondary active sulfate transmembrane transporter activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Secondary active sulfate transmembrane transporter activity (orthology). Reason: Reconstituted human UCP2 exchanges sulfate for phosphate in vitro (Rhea:73391); a substrate-range property of the carrier rather than its physiological role. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. |
| GO:0009409 response to cold | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Response to cold (IBA). Reason: Inherited from a node grounded in UCP1 (MGI:98894). UCP2 does not mediate adaptive thermogenesis; cold-responsiveness as a thermogenic effector is a UCP1 property not supported for UCP2 (cold-induced changes in UCP2 expression in rat hypothalamus do not make it a participant). Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN001183920 SUPPORTS SOURCE BUT NOT TARGET Node placed over the thermogenic UCP1 lineage; UCP2 does not share the thermogenic role. MGI:MGI:98894 SUPPORTS SOURCE BUT NOT TARGET Mouse UCP1, the experimental grounding of the node. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Does not mediate adaptive thermogenesis |
| GO:0009749 response to glucose | IEP PMID:18079609 Nutritional and hormonal regulation of uncoupling protein ge... | KEEP AS NON CORE | Summary: Response to glucose (IEP, rat adipocytes). Reason: Ucp2 expression is induced by this stimulus in rat cells/tissues, and UCP2 in turn dampens nutrient-driven mitochondrial oxidation and ROS. The term is defensible as a physiological response in which UCP2 levels track nutrient/hormone status, but it is downstream of, not part of, its transport function; non-core. Supporting Evidence: PMID:18079609 UCP-2 mRNA expression was more markedly increased by glucose, unsaturated fatty acids, insulin and T3 than UCP-1 or -3 mRNA expression. |
| GO:0015078 proton transmembrane transporter activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Proton transmembrane transporter activity. Reason: UCP2 contributes to proton leak in rat INS-1E cells and reconstituted UCP2 conducts fatty-acid-activated, nucleotide-inhibited proton currents, so the capability is supported. It is non-core because the principal activity is C4-dicarboxylate/phosphate antiport and the physiological weight of the proton conductance is debated. This differs from GO:0017077 (marked over-annotated), which asserts that the leak uncouples oxidative phosphorylation. Supporting Evidence: PMID:21172424 we show that UCP2 contributes to proton leak and attenuates glucose-induced rises in both respiratory activity and the coupling efficiency of oxidative phosphorylation. file:rat/Ucp2/Ucp2-uniprot.txt The proton currents are most likely associated with fatty acid flipping across the inner membrane of mitochondria file:rat/Ucp2/Ucp2-uniprot.txt This activity and its potential regulation by ubiquinones and nucleotides was disputed by later studies, which failed to reproduce the effect on proton conductance under physiological conditions. |
| GO:0015078 proton transmembrane transporter activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Proton transmembrane transporter activity. Reason: UCP2 contributes to proton leak in rat INS-1E cells and reconstituted UCP2 conducts fatty-acid-activated, nucleotide-inhibited proton currents, so the capability is supported. It is non-core because the principal activity is C4-dicarboxylate/phosphate antiport and the physiological weight of the proton conductance is debated. This differs from GO:0017077 (marked over-annotated), which asserts that the leak uncouples oxidative phosphorylation. Supporting Evidence: PMID:21172424 we show that UCP2 contributes to proton leak and attenuates glucose-induced rises in both respiratory activity and the coupling efficiency of oxidative phosphorylation. file:rat/Ucp2/Ucp2-uniprot.txt The proton currents are most likely associated with fatty acid flipping across the inner membrane of mitochondria file:rat/Ucp2/Ucp2-uniprot.txt This activity and its potential regulation by ubiquinones and nucleotides was disputed by later studies, which failed to reproduce the effect on proton conductance under physiological conditions. |
| GO:0015078 proton transmembrane transporter activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Proton transmembrane transporter activity. Reason: UCP2 contributes to proton leak in rat INS-1E cells and reconstituted UCP2 conducts fatty-acid-activated, nucleotide-inhibited proton currents, so the capability is supported. It is non-core because the principal activity is C4-dicarboxylate/phosphate antiport and the physiological weight of the proton conductance is debated. This differs from GO:0017077 (marked over-annotated), which asserts that the leak uncouples oxidative phosphorylation. Supporting Evidence: PMID:21172424 we show that UCP2 contributes to proton leak and attenuates glucose-induced rises in both respiratory activity and the coupling efficiency of oxidative phosphorylation. file:rat/Ucp2/Ucp2-uniprot.txt The proton currents are most likely associated with fatty acid flipping across the inner membrane of mitochondria file:rat/Ucp2/Ucp2-uniprot.txt This activity and its potential regulation by ubiquinones and nucleotides was disputed by later studies, which failed to reproduce the effect on proton conductance under physiological conditions. |
| GO:0015078 proton transmembrane transporter activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Proton transmembrane transporter activity. Reason: UCP2 contributes to proton leak in rat INS-1E cells and reconstituted UCP2 conducts fatty-acid-activated, nucleotide-inhibited proton currents, so the capability is supported. It is non-core because the principal activity is C4-dicarboxylate/phosphate antiport and the physiological weight of the proton conductance is debated. This differs from GO:0017077 (marked over-annotated), which asserts that the leak uncouples oxidative phosphorylation. Supporting Evidence: PMID:21172424 we show that UCP2 contributes to proton leak and attenuates glucose-induced rises in both respiratory activity and the coupling efficiency of oxidative phosphorylation. file:rat/Ucp2/Ucp2-uniprot.txt The proton currents are most likely associated with fatty acid flipping across the inner membrane of mitochondria file:rat/Ucp2/Ucp2-uniprot.txt This activity and its potential regulation by ubiquinones and nucleotides was disputed by later studies, which failed to reproduce the effect on proton conductance under physiological conditions. |
| GO:0015108 chloride transmembrane transporter activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Chloride transmembrane transporter activity (orthology). Reason: Reconstituted UCP2 transports chloride; physiological relevance unclear. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Can unidirectionally transport anions including L-malate, L-aspartate, phosphate and chloride ions |
| GO:0015108 chloride transmembrane transporter activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Chloride transmembrane transporter activity (orthology). Reason: Reconstituted UCP2 transports chloride; physiological relevance unclear. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Can unidirectionally transport anions including L-malate, L-aspartate, phosphate and chloride ions |
| GO:0015131 oxaloacetate transmembrane transporter activity | IEA GO_REF:0000107 | ACCEPT | Summary: Oxaloacetate transmembrane transporter activity (orthology). Reason: Core substrate: reconstituted human UCP2 exchanges oxaloacetate for phosphate plus a proton; the transport residues and SLC25 architecture are conserved in rat UCP2 (high identity to human/mouse UCP2), so the orthology transfer is sound. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015131 oxaloacetate transmembrane transporter activity | ISO GO_REF:0000121 | ACCEPT | Summary: Oxaloacetate transmembrane transporter activity (orthology). Reason: Core substrate: reconstituted human UCP2 exchanges oxaloacetate for phosphate plus a proton; the transport residues and SLC25 architecture are conserved in rat UCP2 (high identity to human/mouse UCP2), so the orthology transfer is sound. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015131 oxaloacetate transmembrane transporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: Oxaloacetate transmembrane transporter activity (orthology). Reason: Core substrate: reconstituted human UCP2 exchanges oxaloacetate for phosphate plus a proton; the transport residues and SLC25 architecture are conserved in rat UCP2 (high identity to human/mouse UCP2), so the orthology transfer is sound. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015140 malate transmembrane transporter activity | IEA GO_REF:0000107 | ACCEPT | Summary: Malate transmembrane transporter activity (orthology). Reason: Core substrate: reconstituted human UCP2 exchanges malate for phosphate plus a proton; the transport residues and SLC25 architecture are conserved in rat UCP2 (high identity to human/mouse UCP2), so the orthology transfer is sound. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015140 malate transmembrane transporter activity | ISO GO_REF:0000121 | ACCEPT | Summary: Malate transmembrane transporter activity (orthology). Reason: Core substrate: reconstituted human UCP2 exchanges malate for phosphate plus a proton; the transport residues and SLC25 architecture are conserved in rat UCP2 (high identity to human/mouse UCP2), so the orthology transfer is sound. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015140 malate transmembrane transporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: Malate transmembrane transporter activity (orthology). Reason: Core substrate: reconstituted human UCP2 exchanges malate for phosphate plus a proton; the transport residues and SLC25 architecture are conserved in rat UCP2 (high identity to human/mouse UCP2), so the orthology transfer is sound. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015183 L-aspartate transmembrane transporter activity | IEA GO_REF:0000107 | ACCEPT | Summary: L-aspartate transmembrane transporter activity (orthology). Reason: Core substrate: reconstituted human UCP2 exchanges L-aspartate for phosphate plus a proton; the transport residues and SLC25 architecture are conserved in rat UCP2 (high identity to human/mouse UCP2), so the orthology transfer is sound. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015183 L-aspartate transmembrane transporter activity | ISO GO_REF:0000121 | ACCEPT | Summary: L-aspartate transmembrane transporter activity (orthology). Reason: Core substrate: reconstituted human UCP2 exchanges L-aspartate for phosphate plus a proton; the transport residues and SLC25 architecture are conserved in rat UCP2 (high identity to human/mouse UCP2), so the orthology transfer is sound. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015183 L-aspartate transmembrane transporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: L-aspartate transmembrane transporter activity (orthology). Reason: Core substrate: reconstituted human UCP2 exchanges L-aspartate for phosphate plus a proton; the transport residues and SLC25 architecture are conserved in rat UCP2 (high identity to human/mouse UCP2), so the orthology transfer is sound. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015297 antiporter activity | IEA GO_REF:0000107 | MODIFY | Summary: Antiporter activity (orthology). Reason: Correct but general: UCP2 exchanges C4 dicarboxylates (malate, oxaloacetate, aspartate, malonate) for phosphate plus a proton, which is dicarboxylate:phosphate antiporter activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P55851 SUPPORTS TRANSFER Orthologous UCP2; transfer is sound, but the term is less specific than warranted. Proposed replacements: dicarboxylate:phosphate antiporter activity Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015297 antiporter activity | ISO GO_REF:0000121 | MODIFY | Summary: Antiporter activity (orthology). Reason: Correct but general: UCP2 exchanges C4 dicarboxylates (malate, oxaloacetate, aspartate, malonate) for phosphate plus a proton, which is dicarboxylate:phosphate antiporter activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P55851 SUPPORTS TRANSFER Orthologous UCP2; transfer is sound, but the term is less specific than warranted. Proposed replacements: dicarboxylate:phosphate antiporter activity Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015297 antiporter activity | ISS GO_REF:0000024 | MODIFY | Summary: Antiporter activity (orthology). Reason: Correct but general: UCP2 exchanges C4 dicarboxylates (malate, oxaloacetate, aspartate, malonate) for phosphate plus a proton, which is dicarboxylate:phosphate antiporter activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P55851 SUPPORTS TRANSFER Orthologous UCP2; transfer is sound, but the term is less specific than warranted. Proposed replacements: dicarboxylate:phosphate antiporter activity Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015740 C4-dicarboxylate transport | IEA GO_REF:0000107 | ACCEPT | Summary: C4-dicarboxylate transport. Reason: Core process: export of C4 Krebs-cycle intermediates from the mitochondrial matrix. Supporting Evidence: PMID:24395786 by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015740 C4-dicarboxylate transport | ISO GO_REF:0000121 | ACCEPT | Summary: C4-dicarboxylate transport. Reason: Core process: export of C4 Krebs-cycle intermediates from the mitochondrial matrix. Supporting Evidence: PMID:24395786 by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015740 C4-dicarboxylate transport | ISS GO_REF:0000024 | ACCEPT | Summary: C4-dicarboxylate transport. Reason: Core process: export of C4 Krebs-cycle intermediates from the mitochondrial matrix. Supporting Evidence: PMID:24395786 by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0015909 long-chain fatty acid transport | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Long-chain fatty acid transport (orthology). Reason: As for the fatty-acid transporter activity: fatty-acid flipping linked to proton conductance; non-core. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt The proton currents are most likely associated with fatty acid flipping across the inner membrane of mitochondria |
| GO:0015909 long-chain fatty acid transport | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Long-chain fatty acid transport (orthology). Reason: As for the fatty-acid transporter activity: fatty-acid flipping linked to proton conductance; non-core. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt The proton currents are most likely associated with fatty acid flipping across the inner membrane of mitochondria |
| GO:0017077 oxidative phosphorylation uncoupler activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Oxidative phosphorylation uncoupler activity (IBA). Reason: The IBA node is grounded in UCP1 (MGI:98894, RGD:3931) and a plant UCP. UCP2 was named by homology with UCP1, but reconstitution and silencing data show it is a C4-dicarboxylate/phosphate antiporter; its proton conductance is real but small (UCP2 levels are hundreds of times lower than UCP1 in brown fat, PMID:18692019) and its uncoupling role is disputed. The transport capability is kept as GO:0015078 (non-core); the claim that it uncouples oxidative phosphorylation as UCP1 does is not supported. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000642156 SUPPORTS SOURCE BUT NOT TARGET Node uncoupler activity grounded in UCP1 and a plant UCP; UCP2 is instead a C4-dicarboxylate/phosphate antiporter whose uncoupling role is disputed. MGI:MGI:98894 SUPPORTS SOURCE BUT NOT TARGET Thermogenic mouse UCP1. RGD:3931 SUPPORTS SOURCE BUT NOT TARGET Thermogenic rat UCP1. Supporting Evidence: PMID:24395786 Here we show that UCP2 is a metabolite transporter that regulates substrate oxidation in mitochondria. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria PMID:18692019 These mitochondrial concentrations are hundreds of times lower than UCP1 in brown adipose tissue |
| GO:0019003 GDP binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: GDP binding (orthology). Reason: Purine nucleotides bind the UCP cavity and inhibit proton conductance; a regulatory binding property, not core. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt 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. |
| GO:0019003 GDP binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: GDP binding (orthology). Reason: Purine nucleotides bind the UCP cavity and inhibit proton conductance; a regulatory binding property, not core. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt 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. |
| GO:0030225 macrophage differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Macrophage differentiation (orthology from mouse). Reason: Mouse data: UCP2 limits ROS to sustain itaconate production and alternative activation of inflammation-resolving macrophages; context-specific and indirect. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Regulates ROS levels and metabolic reprogramming of macrophages during the resolution phase of inflammation |
| GO:0030225 macrophage differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Macrophage differentiation (orthology from mouse). Reason: Mouse data: UCP2 limits ROS to sustain itaconate production and alternative activation of inflammation-resolving macrophages; context-specific and indirect. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Regulates ROS levels and metabolic reprogramming of macrophages during the resolution phase of inflammation |
| GO:0030225 macrophage differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Macrophage differentiation (orthology from mouse). Reason: Mouse data: UCP2 limits ROS to sustain itaconate production and alternative activation of inflammation-resolving macrophages; context-specific and indirect. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Regulates ROS levels and metabolic reprogramming of macrophages during the resolution phase of inflammation |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000107 | MODIFY | Summary: Mitochondrial membrane. Reason: Correct but less specific than the inner-membrane location already carried by this gene (GO:0005743). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P70406 SUPPORTS TRANSFER Orthologous UCP2; transfer is sound, but the term is less specific than warranted. Proposed replacements: mitochondrial inner membrane Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Mitochondrion inner membrane |
| GO:0031966 mitochondrial membrane | ISO GO_REF:0000121 | MODIFY | Summary: Mitochondrial membrane. Reason: Correct but less specific than the inner-membrane location already carried by this gene (GO:0005743). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:109354 SUPPORTS TRANSFER Orthologous UCP2; transfer is sound, but the term is less specific than warranted. Proposed replacements: mitochondrial inner membrane Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Mitochondrion inner membrane |
| GO:0032869 cellular response to insulin stimulus | IEP PMID:18079609 Nutritional and hormonal regulation of uncoupling protein ge... | KEEP AS NON CORE | Summary: Cellular response to insulin stimulus (IEP, rat adipocytes). Reason: Ucp2 expression is induced by this stimulus in rat cells/tissues, and UCP2 in turn dampens nutrient-driven mitochondrial oxidation and ROS. The term is defensible as a physiological response in which UCP2 levels track nutrient/hormone status, but it is downstream of, not part of, its transport function; non-core. Supporting Evidence: PMID:18079609 UCP-2 mRNA expression was more markedly increased by glucose, unsaturated fatty acids, insulin and T3 than UCP-1 or -3 mRNA expression. |
| GO:0032870 cellular response to hormone stimulus | IEP PMID:18079609 Nutritional and hormonal regulation of uncoupling protein ge... | KEEP AS NON CORE | Summary: Cellular response to hormone stimulus (IEP, rat adipocytes). Reason: Ucp2 expression is induced by this stimulus in rat cells/tissues, and UCP2 in turn dampens nutrient-driven mitochondrial oxidation and ROS. The term is defensible as a physiological response in which UCP2 levels track nutrient/hormone status, but it is downstream of, not part of, its transport function; non-core. Supporting Evidence: PMID:18079609 UCP-2 mRNA expression was more markedly increased by glucose, unsaturated fatty acids, insulin and T3 than UCP-1 or -3 mRNA expression. |
| GO:0034198 cellular response to amino acid starvation | IEP PMID:18692019 Dynamic regulation of uncoupling protein 2 content in INS-1E... | MARK AS OVER ANNOTATED | Summary: Cellular response to amino acid starvation (IEP, INS-1E cells). Reason: In rat INS-1E cells, omitting glutamine from the medium lowered UCP2 protein without changing mRNA, reflecting glutamine-dependent translation of the Ucp2 mRNA combined with a ~1 h protein half-life. UCP2 is the object of this regulation, not a participant in an amino-acid-starvation response; over-annotation. Supporting Evidence: PMID:18692019 Omission of glutamine from the medium resulted in decreases in UCP2 in cells and mitochondria (Fig. 2A and B) without affecting Ucp2 mRNA levels (Fig. 2C). PMID:18692019 UCP2 was found to have a short half-life of approximately 1 h (Fig. 4A, B) |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Protein homodimerization activity (orthology). Reason: UCP2 self-associates and appears to function as a dimer of dimers; a structural property rather than its function. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Homotetramer. Adopts an asymmetrical dimer of dimers functional form. |
| GO:0042803 protein homodimerization activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Protein homodimerization activity (orthology). Reason: UCP2 self-associates and appears to function as a dimer of dimers; a structural property rather than its function. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Homotetramer. Adopts an asymmetrical dimer of dimers functional form. |
| GO:0042803 protein homodimerization activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Protein homodimerization activity (orthology). Reason: UCP2 self-associates and appears to function as a dimer of dimers; a structural property rather than its function. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Homotetramer. Adopts an asymmetrical dimer of dimers functional form. |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:18703058 UCP2 protects hypothalamic cells from TNF-alpha-induced dama... | KEEP AS NON CORE | Summary: Negative regulation of apoptotic process (IMP, rat hypothalamus). Reason: Antisense knockdown of UCP2 in rat hypothalamus enhanced TNF-alpha-induced oxidative and pro-apoptotic damage. Consistent with UCP2 lowering mitochondrial ROS; an indirect, protective effect, non-core. Supporting Evidence: PMID:18703058 The inhibition of UCP2 expression by an antisense oligonucleotide enhanced the damaging effects of TNF-alpha. PMID:18703058 UCP2 acts as a protective factor against cellular damage induced by an inflammatory stimulus in the hypothalamus. |
| GO:0043524 negative regulation of neuron apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of neuron apoptotic process (orthology from mouse). Reason: Mouse loss-of-function data place UCP2 upstream of neuronal survival, consistent with the rat hypothalamic antisense data; an indirect ROS-related effect, non-core. Supporting Evidence: PMID:18703058 UCP2 acts as a protective factor against cellular damage induced by an inflammatory stimulus in the hypothalamus. file:rat/Ucp2/Ucp2-uniprot.txt 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 |
| GO:0051881 regulation of mitochondrial membrane potential | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Regulation of mitochondrial membrane potential (orthology). Reason: UCP2 silencing raises inner-membrane potential and ATP:ADP ratio in glucose-grown cells; an indirect consequence of C4-metabolite export (and possibly proton leak). Non-core. Supporting Evidence: PMID:24395786 showed a higher inner mitochondrial membrane potential and ATP:ADP ratio associated with a lower lactate release. PMID:21172424 we show that UCP2 contributes to proton leak and attenuates glucose-induced rises in both respiratory activity and the coupling efficiency of oxidative phosphorylation. |
| GO:0051881 regulation of mitochondrial membrane potential | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of mitochondrial membrane potential (orthology). Reason: UCP2 silencing raises inner-membrane potential and ATP:ADP ratio in glucose-grown cells; an indirect consequence of C4-metabolite export (and possibly proton leak). Non-core. Supporting Evidence: PMID:24395786 showed a higher inner mitochondrial membrane potential and ATP:ADP ratio associated with a lower lactate release. PMID:21172424 we show that UCP2 contributes to proton leak and attenuates glucose-induced rises in both respiratory activity and the coupling efficiency of oxidative phosphorylation. |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | TOO GENERAL | Summary: Transmembrane transport (InterPro). Reason: True but uninformative; GO:0071423 malate transmembrane transport and GO:1990542 mitochondrial transmembrane transport, accepted in this review, already entail it. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:0061179 negative regulation of insulin secretion involved in cellular response to glucose stimulus | IMP PMID:21172424 Uncoupling protein-2 attenuates glucose-stimulated insulin s... | KEEP AS NON CORE | Summary: Negative regulation of insulin secretion involved in cellular response to glucose stimulus (IMP, INS-1E). Reason: UCP2 knockdown in rat INS-1E insulinoma cells raised glucose-induced respiration and coupling efficiency and improved GSIS, and the improvement was abolished by an antioxidant, indicating that UCP2 restrains GSIS at least partly by lowering mitochondrial ROS. Well supported in the rat beta-cell model, but a cell-type-specific physiological consequence of its mitochondrial carrier activity; non-core. Supporting Evidence: PMID:21172424 we show that UCP2 contributes to proton leak and attenuates glucose-induced rises in both respiratory activity and the coupling efficiency of oxidative phosphorylation. PMID:21172424 We conclude that UCP2 plays both regulatory and protective roles in Ξ² cells by acutely lowering GSIS and chronically preventing oxidative stress. |
| GO:0070542 response to fatty acid | IEP PMID:18079609 Nutritional and hormonal regulation of uncoupling protein ge... | KEEP AS NON CORE | Summary: Response to fatty acid (IEP, rat adipocytes). Reason: Ucp2 expression is induced by this stimulus in rat cells/tissues, and UCP2 in turn dampens nutrient-driven mitochondrial oxidation and ROS. The term is defensible as a physiological response in which UCP2 levels track nutrient/hormone status, but it is downstream of, not part of, its transport function; non-core. Supporting Evidence: PMID:18079609 UCP-2 mRNA expression was more markedly increased by glucose, unsaturated fatty acids, insulin and T3 than UCP-1 or -3 mRNA expression. |
| GO:0070778 L-aspartate transmembrane transport | IEA GO_REF:0000108 | ACCEPT | Summary: L-aspartate transmembrane transport. Reason: Consistent with the aspartate/phosphate exchange activity of UCP2. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. |
| GO:0071284 cellular response to lead ion | IEP PMID:33576715 Mitochondrial uncoupling protein 2 is regulated through hete... | MARK AS OVER ANNOTATED | Summary: Cellular response to lead ion (IEP). Reason: Based only on a change in Ucp2 expression under this condition in a rat model; altered expression shows that Ucp2 is a target of the response, not that it carries out part of it. Over-annotation relative to its function as a mitochondrial C4-dicarboxylate carrier. Supporting Evidence: PMID:33576715 We found that the expression levels of UCP2 and hnRNP K had significant declines in the lead exposure rat hippocampus and PC12 cells. |
| GO:0071333 cellular response to glucose stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cellular response to glucose stimulus. Reason: High glucose raises UCP2 protein in rat INS-1E cells (IEP), and in mouse beta cells and VMH neurons UCP2 shapes the glucose-driven mitochondrial response (orthology rows). A regulatory, cell-type-specific consequence rather than the core activity; non-core. Supporting Evidence: PMID:18692019 doubling glucose concentration to 20 mM increased protein levels 2-fold over control (Fig. 2D) file:rat/Ucp2/Ucp2-uniprot.txt Required for glucose-induced DRP1-dependent mitochondrial fission and neuron activation in the ventromedial nucleus of the hypothalamus (VMH) |
| GO:0071333 cellular response to glucose stimulus | IEP PMID:18692019 Dynamic regulation of uncoupling protein 2 content in INS-1E... | KEEP AS NON CORE | Summary: Cellular response to glucose stimulus. Reason: High glucose raises UCP2 protein in rat INS-1E cells (IEP), and in mouse beta cells and VMH neurons UCP2 shapes the glucose-driven mitochondrial response (orthology rows). A regulatory, cell-type-specific consequence rather than the core activity; non-core. Supporting Evidence: PMID:18692019 doubling glucose concentration to 20 mM increased protein levels 2-fold over control (Fig. 2D) file:rat/Ucp2/Ucp2-uniprot.txt Required for glucose-induced DRP1-dependent mitochondrial fission and neuron activation in the ventromedial nucleus of the hypothalamus (VMH) |
| GO:0071333 cellular response to glucose stimulus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to glucose stimulus. Reason: High glucose raises UCP2 protein in rat INS-1E cells (IEP), and in mouse beta cells and VMH neurons UCP2 shapes the glucose-driven mitochondrial response (orthology rows). A regulatory, cell-type-specific consequence rather than the core activity; non-core. Supporting Evidence: PMID:18692019 doubling glucose concentration to 20 mM increased protein levels 2-fold over control (Fig. 2D) file:rat/Ucp2/Ucp2-uniprot.txt Required for glucose-induced DRP1-dependent mitochondrial fission and neuron activation in the ventromedial nucleus of the hypothalamus (VMH) |
| GO:0071333 cellular response to glucose stimulus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cellular response to glucose stimulus. Reason: High glucose raises UCP2 protein in rat INS-1E cells (IEP), and in mouse beta cells and VMH neurons UCP2 shapes the glucose-driven mitochondrial response (orthology rows). A regulatory, cell-type-specific consequence rather than the core activity; non-core. Supporting Evidence: PMID:18692019 doubling glucose concentration to 20 mM increased protein levels 2-fold over control (Fig. 2D) file:rat/Ucp2/Ucp2-uniprot.txt Required for glucose-induced DRP1-dependent mitochondrial fission and neuron activation in the ventromedial nucleus of the hypothalamus (VMH) |
| GO:0071423 malate transmembrane transport | IEA GO_REF:0000108 | ACCEPT | Summary: Malate transmembrane transport. Reason: Consistent with the malate/phosphate exchange activity of UCP2. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. |
| GO:0071548 response to dexamethasone | IEP PMID:20393169 Antioxidant defenses in the rat placenta in late gestation: ... | MARK AS OVER ANNOTATED | Summary: Response to dexamethasone (IEP, rat placenta). Reason: Based only on a change in Ucp2 expression under this condition in a rat model; altered expression shows that Ucp2 is a target of the response, not that it carries out part of it. Over-annotation relative to its function as a mitochondrial C4-dicarboxylate carrier. Supporting Evidence: PMID:20393169 Dexamethasone treatment reduced fetal-placental growth and LZ expression of Ucp2 but increased JZ expression of Txn1. |
| GO:0072593 reactive oxygen species metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reactive oxygen species metabolic process (orthology). Reason: UCP2 lowers mitochondrial ROS production by limiting Krebs-cycle oxidation (and possibly mild proton leak), shown also in rat INS-1E cells; indirect, non-core. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt 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 PMID:21172424 We conclude that UCP2 plays both regulatory and protective roles in Ξ² cells by acutely lowering GSIS and chronically preventing oxidative stress. |
| GO:0072593 reactive oxygen species metabolic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Reactive oxygen species metabolic process (orthology). Reason: UCP2 lowers mitochondrial ROS production by limiting Krebs-cycle oxidation (and possibly mild proton leak), shown also in rat INS-1E cells; indirect, non-core. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt 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 PMID:21172424 We conclude that UCP2 plays both regulatory and protective roles in Ξ² cells by acutely lowering GSIS and chronically preventing oxidative stress. |
| GO:0072593 reactive oxygen species metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Reactive oxygen species metabolic process (orthology). Reason: UCP2 lowers mitochondrial ROS production by limiting Krebs-cycle oxidation (and possibly mild proton leak), shown also in rat INS-1E cells; indirect, non-core. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt 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 PMID:21172424 We conclude that UCP2 plays both regulatory and protective roles in Ξ² cells by acutely lowering GSIS and chronically preventing oxidative stress. |
| GO:0097421 liver regeneration | IEP PMID:19104935 Protection of regenerating liver after partial hepatectomy f... | MARK AS OVER ANNOTATED | Summary: Liver regeneration (IEP). Reason: Ucp2 expression rises in regenerating rat liver after partial hepatectomy; expression change alone does not show that UCP2 carries out part of liver regeneration (the paper concerns protection from CCl4 toxicity). Over-annotation. Supporting Evidence: PMID:19104935 UCP(2) expression was markedly elevated in the regenerating liver, and further increased after CCl(4) intoxication. |
| GO:0110099 negative regulation of calcium import into the mitochondrion | IEA GO_REF:0000107 | UNDECIDED | Summary: Negative regulation of calcium import into the mitochondrion (orthology from human IDA). Reason: Transferred from a human IDA (PRMT1/MICU1 study) whose abstract describes UCP2/3 restoring, rather than inhibiting, mitochondrial Ca2+ uptake of methylated MICU1. The direction of the effect cannot be adjudicated without the source full text; left undecided, as in the human review. Propagation Review Root cause: UNRESOLVED Failure modes: REGULATORY SIGN INVERSION Sources checked: UniProtKB:P55851 UNRESOLVED Human IDA (PRMT1/MICU1 study); direction of the effect on mitochondrial Ca2+ uptake unclear from the abstract. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Interacts with MICU1 (when methylated); leading to decrease the calcium sensitivity of MICU1. |
| GO:0110099 negative regulation of calcium import into the mitochondrion | ISO GO_REF:0000121 | UNDECIDED | Summary: Negative regulation of calcium import into the mitochondrion (orthology from human IDA). Reason: Transferred from a human IDA (PRMT1/MICU1 study) whose abstract describes UCP2/3 restoring, rather than inhibiting, mitochondrial Ca2+ uptake of methylated MICU1. The direction of the effect cannot be adjudicated without the source full text; left undecided, as in the human review. Propagation Review Root cause: UNRESOLVED Failure modes: REGULATORY SIGN INVERSION Sources checked: UniProtKB:P55851 UNRESOLVED Human IDA (PRMT1/MICU1 study); direction of the effect on mitochondrial Ca2+ uptake unclear from the abstract. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Interacts with MICU1 (when methylated); leading to decrease the calcium sensitivity of MICU1. |
| GO:0120162 positive regulation of cold-induced thermogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Positive regulation of cold-induced thermogenesis. Reason: Ucp2-null mice fail to adapt BAT thermogenesis to cold because fuel use shifts toward glucose; UCP2 favours fatty-acid utilisation rather than acting as a thermogenic uncoupler. An indirect metabolic contribution; non-core. Supporting Evidence: PMID:28130074 We conclude that UCP2 regulates BAT thermogenesis by favouring the utilization of NEFA, a process required for the adaptation to cold. |
| GO:0120162 positive regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of cold-induced thermogenesis. Reason: Ucp2-null mice fail to adapt BAT thermogenesis to cold because fuel use shifts toward glucose; UCP2 favours fatty-acid utilisation rather than acting as a thermogenic uncoupler. An indirect metabolic contribution; non-core. Supporting Evidence: PMID:28130074 We conclude that UCP2 regulates BAT thermogenesis by favouring the utilization of NEFA, a process required for the adaptation to cold. |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of cold-induced thermogenesis. Reason: Ucp2-null mice fail to adapt BAT thermogenesis to cold because fuel use shifts toward glucose; UCP2 favours fatty-acid utilisation rather than acting as a thermogenic uncoupler. An indirect metabolic contribution; non-core. Supporting Evidence: PMID:28130074 We conclude that UCP2 regulates BAT thermogenesis by favouring the utilization of NEFA, a process required for the adaptation to cold. |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS PMID:28130074 Loss of UCP2 impairs cold-induced non-shivering thermogenesi... | KEEP AS NON CORE | Summary: Positive regulation of cold-induced thermogenesis. Reason: Ucp2-null mice fail to adapt BAT thermogenesis to cold because fuel use shifts toward glucose; UCP2 favours fatty-acid utilisation rather than acting as a thermogenic uncoupler. An indirect metabolic contribution; non-core. Supporting Evidence: PMID:28130074 We conclude that UCP2 regulates BAT thermogenesis by favouring the utilization of NEFA, a process required for the adaptation to cold. |
| GO:0140787 phosphate ion uniporter activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Phosphate ion uniporter activity (orthology). Reason: UCP2 can unidirectionally transport phosphate in reconstitution; physiologically phosphate moves as the counter-substrate of the antiport. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Can unidirectionally transport anions including L-malate, L-aspartate, phosphate and chloride ions |
| GO:0140787 phosphate ion uniporter activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Phosphate ion uniporter activity (orthology). Reason: UCP2 can unidirectionally transport phosphate in reconstitution; physiologically phosphate moves as the counter-substrate of the antiport. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Can unidirectionally transport anions including L-malate, L-aspartate, phosphate and chloride ions |
| GO:0140787 phosphate ion uniporter activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Phosphate ion uniporter activity (orthology). Reason: UCP2 can unidirectionally transport phosphate in reconstitution; physiologically phosphate moves as the counter-substrate of the antiport. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Can unidirectionally transport anions including L-malate, L-aspartate, phosphate and chloride ions |
| GO:1902356 oxaloacetate(2-) transmembrane transport | IEA GO_REF:0000108 | ACCEPT | Summary: Oxaloacetate(2-) transmembrane transport. Reason: Consistent with the oxaloacetate/phosphate exchange activity of UCP2. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. |
| GO:1902358 sulfate transmembrane transport | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Sulfate transmembrane transport. Reason: In vitro substrate property; non-core. Supporting Evidence: PMID:24395786 UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. |
| GO:1902476 chloride transmembrane transport | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Chloride transmembrane transport. Reason: In vitro property; non-core. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Can unidirectionally transport anions including L-malate, L-aspartate, phosphate and chloride ions |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Proton transmembrane transport. Reason: Consistent with the measured proton leak of UCP2 (rat INS-1E cells); debated physiological importance, non-core. Supporting Evidence: PMID:21172424 we show that UCP2 contributes to proton leak and attenuates glucose-induced rises in both respiratory activity and the coupling efficiency of oxidative phosphorylation. |
| GO:1990542 mitochondrial transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial transmembrane transport. Reason: Correct: UCP2 moves C4 metabolites and phosphate across the inner mitochondrial membrane. Supporting Evidence: PMID:24395786 by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:1990542 mitochondrial transmembrane transport | IEA GO_REF:0000107 | ACCEPT | Summary: Mitochondrial transmembrane transport. Reason: Correct: UCP2 moves C4 metabolites and phosphate across the inner mitochondrial membrane. Supporting Evidence: PMID:24395786 by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:1990542 mitochondrial transmembrane transport | ISO GO_REF:0000121 | ACCEPT | Summary: Mitochondrial transmembrane transport. Reason: Correct: UCP2 moves C4 metabolites and phosphate across the inner mitochondrial membrane. Supporting Evidence: PMID:24395786 by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:1990542 mitochondrial transmembrane transport | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial transmembrane transport. Reason: Correct: UCP2 moves C4 metabolites and phosphate across the inner mitochondrial membrane. Supporting Evidence: PMID:24395786 by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. file:rat/Ucp2/Ucp2-uniprot.txt Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria |
| GO:1990845 adaptive thermogenesis | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Adaptive thermogenesis (IBA). Reason: The IBA reflects the UCP1 thermogenic function at the family node (MGI:98894); UCP2 does not mediate adaptive thermogenesis and is present at far lower levels than UCP1. Its effect on cold adaptation is via fuel selection (kept as GO:0120162, non-core). Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN001183920 SUPPORTS SOURCE BUT NOT TARGET Node placed over the thermogenic UCP1 lineage; UCP2 does not share the thermogenic role. MGI:MGI:98894 SUPPORTS SOURCE BUT NOT TARGET Mouse UCP1, the experimental grounding of the node. Supporting Evidence: file:rat/Ucp2/Ucp2-uniprot.txt Does not mediate adaptive thermogenesis PMID:28130074 We conclude that UCP2 regulates BAT thermogenesis by favouring the utilization of NEFA, a process required for the adaptation to cold. |
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Download this section (compressed HTML)Q: This review takes C4-dicarboxylate:phosphate antiport as UCP2's core activity and keeps proton conductance (GO:0015078) as non-core. The fatty-acid-activated proton-leak reading is still actively defended; should the core function instead record both activities, or proton transport alone?
Q: In rat INS-1E cells, how much of the UCP2-dependent attenuation of glucose-stimulated insulin secretion reflects C4-dicarboxylate export versus fatty-acid-activated proton leak?
Q: What degradation machinery outside the mitochondrion (proteasome-dependent turnover) sets the ~1 h half-life of UCP2, and is it regulated by nutrients?
Experiment: Re-express wild-type or transport-dead UCP2 in UCP2-knockdown INS-1E cells and measure malate/aspartate efflux, proton leak and GSIS to test which activity accounts for the secretion phenotype.
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