ADP/ATP translocase 1 (ANT1, AAC1) is the heart- and skeletal-muscle-enriched isoform of the mitochondrial ADP/ATP carrier, a six-transmembrane member of the mitochondrial carrier family (SLC25) located in the mitochondrial inner membrane. Working as a monomer with a single substrate-binding site and an alternating-access mechanism, it exchanges cytosolic ADP for matrix ATP, supplying ATP synthase with substrate and exporting the ATP made by oxidative phosphorylation. It also mediates a fatty-acid-dependent proton leak that uncouples respiration from ATP synthesis and is negatively regulated by ongoing ADP/ATP exchange. ANT binds cyclophilin D and modulates, without being essential for, the mitochondrial permeability transition pore, and it promotes PINK1/parkin mitophagy through TIM44 independently of nucleotide exchange. In rat, ANT1 expression rises during postnatal heart maturation, and cardiac overexpression enhances contractile function and protects cardiomyocytes from TGF-beta1-induced, pore-dependent apoptosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001889 liver development | IEP PMID:9468308 Muscle/heart isoform of mitochondrial adenine nucleotide tra... | MARK AS OVER ANNOTATED | Summary: Expression study: ANT1 is transiently expressed in perinatal rat liver. Reason: IEP evidence shows only that Ant1 mRNA/protein rises during perinatal liver maturation; it does not show that ANT1 performs any step of liver development. The paper itself suggests a role in maturation of mitochondrial respiration, which is captured by the core transport activity. Supporting Evidence: PMID:9468308 in contrast to adult liver, perinatal liver expressed the ANT1 isoform at the mRNA and protein level |
| GO:0005471 ATP:ADP antiporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: ATP:ADP antiporter activity is the defining activity of ANT1. (IBA). Reason: Slc25a4 is the heart/muscle ADP/ATP carrier; the carrier family signature, conserved ADP-binding residues and direct transport assays on the human and mouse orthologs establish ADP/ATP exchange across the inner membrane, and rat ANT1 overexpression increases mitochondrial ATP/ADP transport. Core function. Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation UniProtKB:Q05962 Belongs to the mitochondrial carrier (TC 2.A.29) family. |
| GO:0005471 ATP:ADP antiporter activity | IEA GO_REF:0000002 | ACCEPT | Summary: ATP:ADP antiporter activity is the defining activity of ANT1. (IEA). Reason: Slc25a4 is the heart/muscle ADP/ATP carrier; the carrier family signature, conserved ADP-binding residues and direct transport assays on the human and mouse orthologs establish ADP/ATP exchange across the inner membrane, and rat ANT1 overexpression increases mitochondrial ATP/ADP transport. Core function. Supporting Evidence: UniProtKB:Q05962 Belongs to the mitochondrial carrier (TC 2.A.29) family. UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell |
| GO:0005471 ATP:ADP antiporter activity | ISO GO_REF:0000121 | ACCEPT | Summary: ATP:ADP antiporter activity is the defining activity of ANT1. (ISO). Reason: Slc25a4 is the heart/muscle ADP/ATP carrier; the carrier family signature, conserved ADP-binding residues and direct transport assays on the human and mouse orthologs establish ADP/ATP exchange across the inner membrane, and rat ANT1 overexpression increases mitochondrial ATP/ADP transport. Core function. Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation PMID:21325829 These data reveal a close association of elevated mitochondrial ATP/ADP transportation via ANT1 with increased contractile function. |
| GO:0005471 ATP:ADP antiporter activity | ISO GO_REF:0000121 | ACCEPT | Summary: ATP:ADP antiporter activity is the defining activity of ANT1. (ISO). Reason: Slc25a4 is the heart/muscle ADP/ATP carrier; the carrier family signature, conserved ADP-binding residues and direct transport assays on the human and mouse orthologs establish ADP/ATP exchange across the inner membrane, and rat ANT1 overexpression increases mitochondrial ATP/ADP transport. Core function. Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation PMID:21325829 These data reveal a close association of elevated mitochondrial ATP/ADP transportation via ANT1 with increased contractile function. |
| GO:0005471 ATP:ADP antiporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: ATP:ADP antiporter activity is the defining activity of ANT1. (ISS). Reason: Slc25a4 is the heart/muscle ADP/ATP carrier; the carrier family signature, conserved ADP-binding residues and direct transport assays on the human and mouse orthologs establish ADP/ATP exchange across the inner membrane, and rat ANT1 overexpression increases mitochondrial ATP/ADP transport. Core function. Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation PMID:21325829 These data reveal a close association of elevated mitochondrial ATP/ADP transportation via ANT1 with increased contractile function. |
| GO:0005739 mitochondrion | ISO GO_REF:0000121 | ACCEPT | Summary: Mitochondrion (ISO from human SLC25A4). Reason: Root organelle term from an ortholog transfer. Checked: the human source and the rat protein are integral inner-membrane carriers with six TM helices, so the mitochondrion claim holds; the sub-compartment (mitochondrial inner membrane) is already carried by several rows including rat IDA. Supporting Evidence: UniProtKB:Q05962 Mitochondrion inner membrane |
| GO:0005741 mitochondrial outer membrane | IDA PMID:18385140 Dual specificity phosphatases 18 and 21 target to opposing s... | MARK AS OVER ANNOTATED | Summary: Outer membrane location inferred from rat kidney/testis subfractionation in which ANT served as an inner-membrane marker. Reason: I read the full text. The paper used anti-ANT only as the inner-membrane marker and explicitly attributes ANT signal in outer-membrane fractions to co-fractionation at OM/IM contact sites, not to residence in the outer membrane. The antibody was not isoform-specific. ANT1 is an inner-membrane carrier; the outer-membrane annotation over-interprets a marker blot. Supporting Evidence: PMID:18385140 The mitochondrial OM marker VDAC and the IM marker adenine nucleotide transporter (ANT) are both found at OM/IM contact sites; therefore, they can be found in both membrane fractions. |
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial inner membrane (IBA). Reason: Mitochondrial carrier family member with six transmembrane helices and matrix/intermembrane topology; inner-membrane residence is the location where ADP/ATP exchange occurs. Core location. Supporting Evidence: UniProtKB:Q05962 Mitochondrion inner membrane UniProtKB:Q05962 Belongs to the mitochondrial carrier (TC 2.A.29) family. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:18385140 Dual specificity phosphatases 18 and 21 target to opposing s... | ACCEPT | Summary: Inner-membrane location from rat kidney/testis mitochondrial subfractionation. Reason: ANT was used as the inner-membrane marker in rigorous submitochondrial fractionation of rat tissue. Consistent with six-TM carrier topology. Core location. Supporting Evidence: PMID:18385140 The mitochondrial OM marker VDAC and the IM marker adenine nucleotide transporter (ANT) are both found at OM/IM contact sites; therefore, they can be found in both membrane fractions. UniProtKB:Q05962 Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IDA PMID:9820802 Direct demonstration of a specific interaction between cyclo... | ACCEPT | Summary: Inner-membrane location: CyP-D pulls down ANT from purified liver inner mitochondrial membranes. Reason: Liver IMM fractions contain ANT detected by immunoblot. Adult liver expresses mainly ANT2, and the antibody was not shown to be isoform-specific (abstract only), but inner-membrane residence of ANT1 is independently established by its topology and by the rat fractionation in PMID:18385140, so the location is accepted. Supporting Evidence: PMID:9820802 Immobilized GST-CyP-D avidly bound a single 30 kDa protein present in Triton X-100-solubilized IMMs; immunoblotting showed this to be the adenine nucleotide translocase (ANT). UniProtKB:Q05962 Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrial inner membrane (IEA). Reason: Mitochondrial carrier family member with six transmembrane helices and matrix/intermembrane topology; inner-membrane residence is the location where ADP/ATP exchange occurs. Core location. Supporting Evidence: UniProtKB:Q05962 Mitochondrion inner membrane UniProtKB:Q05962 Belongs to the mitochondrial carrier (TC 2.A.29) family. |
| GO:0005743 mitochondrial inner membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Mitochondrial inner membrane (ISO). Reason: Mitochondrial carrier family member with six transmembrane helices and matrix/intermembrane topology; inner-membrane residence is the location where ADP/ATP exchange occurs. Core location. Supporting Evidence: UniProtKB:Q05962 Mitochondrion inner membrane UniProtKB:Q05962 Belongs to the mitochondrial carrier (TC 2.A.29) family. |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial inner membrane (ISS). Reason: Mitochondrial carrier family member with six transmembrane helices and matrix/intermembrane topology; inner-membrane residence is the location where ADP/ATP exchange occurs. Core location. Supporting Evidence: UniProtKB:Q05962 Mitochondrion inner membrane UniProtKB:Q05962 Belongs to the mitochondrial carrier (TC 2.A.29) family. |
| GO:0005757 mitochondrial permeability transition pore complex | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Part of the mitochondrial permeability transition pore complex (IBA). Reason: ANT binds cyclophilin D and ANT ligands modulate pore opening, and GO defines the complex as containing ANT; but genetic ablation of both liver ANTs shows ANT is not essential for permeability transition, only a regulator. The membership claim is retained as non-core and contested. Supporting Evidence: PMID:9820802 Immobilized GST-CyP-D avidly bound a single 30 kDa protein present in Triton X-100-solubilized IMMs; immunoblotting showed this to be the adenine nucleotide translocase (ANT). PMID:14749836 ANTs are non-essential structural components of the mtPTP, although they do contribute to its regulation. |
| GO:0005757 mitochondrial permeability transition pore complex | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Part of the mitochondrial permeability transition pore complex (ISO). Reason: ANT binds cyclophilin D and ANT ligands modulate pore opening, and GO defines the complex as containing ANT; but genetic ablation of both liver ANTs shows ANT is not essential for permeability transition, only a regulator. The membership claim is retained as non-core and contested. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:1353495 SUPPORTS TRANSFER Ortholog annotation reflects ANT-cyclophilin D association and mPTP regulation; transfer is sound but the role is regulatory and non-core. Supporting Evidence: PMID:9820802 Immobilized GST-CyP-D avidly bound a single 30 kDa protein present in Triton X-100-solubilized IMMs; immunoblotting showed this to be the adenine nucleotide translocase (ANT). PMID:14749836 ANTs are non-essential structural components of the mtPTP, although they do contribute to its regulation. |
| GO:0005757 mitochondrial permeability transition pore complex | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Part of the mitochondrial permeability transition pore complex (ISS). Reason: ANT binds cyclophilin D and ANT ligands modulate pore opening, and GO defines the complex as containing ANT; but genetic ablation of both liver ANTs shows ANT is not essential for permeability transition, only a regulator. The membership claim is retained as non-core and contested. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P48962 SUPPORTS TRANSFER Ortholog annotation reflects ANT-cyclophilin D association and mPTP regulation; transfer is sound but the role is regulatory and non-core. Supporting Evidence: PMID:9820802 Immobilized GST-CyP-D avidly bound a single 30 kDa protein present in Triton X-100-solubilized IMMs; immunoblotting showed this to be the adenine nucleotide translocase (ANT). PMID:14749836 ANTs are non-essential structural components of the mtPTP, although they do contribute to its regulation. |
| GO:0007507 heart development | IEP PMID:12676547 Expression of mitochondrial uncoupling protein 3 and adenine... | MARK AS OVER ANNOTATED | Summary: Expression study: Ant1 expression increases during postnatal rat heart development. Reason: IEP evidence documents a postnatal rise in Ant1 mRNA in left-ventricular myocardium. Expression correlation does not show that ANT1 performs a step of heart development; the role in mitochondrial energy conversion is captured by the transport activity. Supporting Evidence: PMID:12676547 Postnatal activation in the expression of UCP2, UCP3, ANT1 and PPARalpha genes resulted in the expression maxima between days 20 and 30. |
| GO:0008637 apoptotic mitochondrial changes | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Acts upstream of or within apoptotic mitochondrial changes (ISO from mouse). Reason: ANT influences permeability transition and mitochondrial membrane potential during apoptosis; this is a regulatory, context-dependent role downstream of its carrier conformations, not the core function. Supporting Evidence: PMID:14749836 ANTs are non-essential structural components of the mtPTP, although they do contribute to its regulation. PMID:22564366 Heart-specific overexpression of ANT1 leads to a reduced apoptotic response to TGFΞ²(1) by preservation of the mitochondrial membrane potential, resistance to MPTP opening and altered TGFΞ² signaling. |
| GO:0010667 negative regulation of cardiac muscle cell apoptotic process | IDA PMID:22564366 Transgenic overexpression of the adenine nucleotide transloc... | KEEP AS NON CORE | Summary: ANT1 overexpression protects rat cardiomyocytes from TGFb1-induced apoptosis. Reason: Rat transgenic overexpression reduces apoptosis via preserved membrane potential and reduced MPTP opening. This is a gain-of-function phenotype consistent with ANT modulation of the pore; retained as non-core (abstract only). Supporting Evidence: PMID:22564366 Heart-specific overexpression of ANT1 leads to a reduced apoptotic response to TGFΞ²(1) by preservation of the mitochondrial membrane potential, resistance to MPTP opening and altered TGFΞ² signaling. |
| GO:0015078 proton transmembrane transporter activity | ISO GO_REF:0000121 | ACCEPT | Summary: Proton transmembrane transporter activity (ISO from mouse). Reason: Direct patch-clamp of mouse inner membranes shows AAC conducts a fatty-acid-dependent H+ current that is largely lost in AAC1-null heart and muscle; rat muscle mitochondria show carboxyatractylate-sensitive proton conductance. This second transport mode is a genuine activity of ANT1. Supporting Evidence: PMID:31341297 The AAC-mediated H+ current requires free fatty acids and resembles the H+ leak via the thermogenic uncoupling protein 1 found in brown fat. PMID:18251717 an endogenously generated activator stimulates proton conductance catalysed partly by UCP3 and partly by the adenine nucleotide translocase |
| GO:0015217 ADP transmembrane transporter activity | ISO GO_REF:0000121 | MODIFY | Summary: ADP transmembrane transporter activity (ISO). Reason: True but general: ANT1 transports ADP strictly in exchange for ATP. GO:0005471 ATP:ADP antiporter activity is an is_a descendant of GO:0015217 (checked with OAK) and is already carried by the IBA/IEA/ISO/ISS rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P12235 SUPPORTS TRANSFER Human SLC25A4 ADP transport is established; the transferred term is less precise than the antiport activity. Proposed replacements: ATP:ADP antiporter activity Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation |
| GO:0015217 ADP transmembrane transporter activity | ISS GO_REF:0000024 | MODIFY | Summary: ADP transmembrane transporter activity (ISS). Reason: True but general: ANT1 transports ADP strictly in exchange for ATP. GO:0005471 ATP:ADP antiporter activity is an is_a descendant of GO:0015217 (checked with OAK) and is already carried by the IBA/IEA/ISO/ISS rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P12235 SUPPORTS TRANSFER Human SLC25A4 ADP transport is established; the transferred term is less precise than the antiport activity. Proposed replacements: ATP:ADP antiporter activity Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation |
| GO:0015866 ADP transport | ISO GO_REF:0000121 | MODIFY | Summary: ADP transport (ISO). Reason: True but general: the ADP transport mediated by ANT1 is import across the mitochondrial inner membrane. GO:0140021 mitochondrial ADP transmembrane transport is an is_a descendant of GO:0015866 (checked with OAK) and is already carried by other rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P12235 SUPPORTS TRANSFER Source function is sound; refined to the mitochondrial transmembrane term. Proposed replacements: mitochondrial ADP transmembrane transport Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell |
| GO:0015866 ADP transport | ISS GO_REF:0000024 | MODIFY | Summary: ADP transport (ISS). Reason: True but general: the ADP transport mediated by ANT1 is import across the mitochondrial inner membrane. GO:0140021 mitochondrial ADP transmembrane transport is an is_a descendant of GO:0015866 (checked with OAK) and is already carried by other rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P12235 SUPPORTS TRANSFER Source function is sound; refined to the mitochondrial transmembrane term. Proposed replacements: mitochondrial ADP transmembrane transport Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: Membrane (IEA). Reason: True but uninformative: the membrane in which ANT1 resides is the mitochondrial inner membrane (GO:0005743, a part_of descendant of membrane, already carried by IDA and other rows). UniProt notes possible non-mitochondrial membranes by similarity, but no rat evidence supports that. Proposed replacements: mitochondrial inner membrane Supporting Evidence: UniProtKB:Q05962 Mitochondrion inner membrane |
| GO:0016020 membrane | ISO GO_REF:0000121 | MODIFY | Summary: Membrane (ISO). Reason: True but uninformative: the membrane in which ANT1 resides is the mitochondrial inner membrane (GO:0005743, a part_of descendant of membrane, already carried by IDA and other rows). UniProt notes possible non-mitochondrial membranes by similarity, but no rat evidence supports that. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P12235 SUPPORTS TRANSFER Source membrane localization is correct but less precise than the known inner-membrane location. Proposed replacements: mitochondrial inner membrane Supporting Evidence: UniProtKB:Q05962 Mitochondrion inner membrane |
| GO:0016020 membrane | ISS GO_REF:0000024 | MODIFY | Summary: Membrane (ISS). Reason: True but uninformative: the membrane in which ANT1 resides is the mitochondrial inner membrane (GO:0005743, a part_of descendant of membrane, already carried by IDA and other rows). UniProt notes possible non-mitochondrial membranes by similarity, but no rat evidence supports that. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P12235 SUPPORTS TRANSFER Source membrane localization is correct but less precise than the known inner-membrane location. Proposed replacements: mitochondrial inner membrane Supporting Evidence: UniProtKB:Q05962 Mitochondrion inner membrane |
| GO:0017077 oxidative phosphorylation uncoupler activity | ISO GO_REF:0000121 | ACCEPT | Summary: Oxidative phosphorylation uncoupler activity (ISO). Reason: AAC1 mediates fatty-acid-activated H+ leak from the intermembrane space into the matrix, which uncouples respiration from ATP synthesis; in rat muscle mitochondria part of the inducible proton conductance is carboxyatractylate/bongkrekate sensitive. Second core transport mode. Supporting Evidence: PMID:31341297 The AAC-mediated H+ current requires free fatty acids and resembles the H+ leak via the thermogenic uncoupling protein 1 found in brown fat. PMID:31341297 By mediating two distinct transport modes, ADP/ATP exchange and H+ leak, AAC connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria. PMID:18251717 an endogenously generated activator stimulates proton conductance catalysed partly by UCP3 and partly by the adenine nucleotide translocase |
| GO:0017077 oxidative phosphorylation uncoupler activity | ISS GO_REF:0000024 | ACCEPT | Summary: Oxidative phosphorylation uncoupler activity (ISS). Reason: AAC1 mediates fatty-acid-activated H+ leak from the intermembrane space into the matrix, which uncouples respiration from ATP synthesis; in rat muscle mitochondria part of the inducible proton conductance is carboxyatractylate/bongkrekate sensitive. Second core transport mode. Supporting Evidence: PMID:31341297 The AAC-mediated H+ current requires free fatty acids and resembles the H+ leak via the thermogenic uncoupling protein 1 found in brown fat. PMID:31341297 By mediating two distinct transport modes, ADP/ATP exchange and H+ leak, AAC connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria. PMID:18251717 an endogenously generated activator stimulates proton conductance catalysed partly by UCP3 and partly by the adenine nucleotide translocase |
| GO:0019899 enzyme binding | IPI PMID:12077116 Mitochondrial targeted cyclophilin D protects cells from cel... | KEEP AS NON CORE | Summary: Enzyme binding: ANT binds cyclophilin D (Ppif) in GST pull-down. Reason: CyPD-ANT binding is reproducible (also PMID:9820802) and relevant to mPTP regulation; it is a partner interaction rather than ANT1 core activity. Abstract-only; isoform and species of the ANT tested not stated in the abstract. Supporting Evidence: PMID:12077116 CyPD binding to the adenine nucleotide translocator (ANT), which is considered to be the core component of the mPTP, is not affected by the loss of PPIase activity PMID:9820802 Immobilized GST-CyP-D avidly bound a single 30 kDa protein present in Triton X-100-solubilized IMMs; immunoblotting showed this to be the adenine nucleotide translocase (ANT). |
| GO:0031966 mitochondrial membrane | ISS GO_REF:0000024 | MODIFY | Summary: Mitochondrial membrane (ISS from bovine AAC1). Reason: True but general: ANT1 is an integral inner-membrane protein. GO:0005743 mitochondrial inner membrane is a descendant of GO:0031966 (checked with OAK) and is already carried by several rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P02722 SUPPORTS TRANSFER Bovine AAC1 crystal structure places it in the inner membrane; transferred term is less precise. Proposed replacements: mitochondrial inner membrane Supporting Evidence: UniProtKB:Q05962 Mitochondrion inner membrane |
| GO:0045121 membrane raft | IDA PMID:14499952 Proteomic characterisation of neuronal sphingolipid-choleste... | UNDECIDED | Summary: Membrane raft: detergent-resistant membrane proteomics of rat hippocampal neurons. Reason: Abstract only; the abstract does not mention ANT and the identification/validation of ANT in the raft fraction cannot be inspected. Mitochondrial inner-membrane carriers are frequent co-purifying contaminants of detergent-resistant membrane preparations, and no other evidence places ANT1 in plasma-membrane rafts. Cannot verify, so left undecided rather than removed. Supporting Evidence: file:rat/Slc25a4/Slc25a4-deep-research-manual.md No other source places ANT1 in plasma-membrane rafts |
| GO:0046902 regulation of mitochondrial membrane permeability | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Regulation of mitochondrial membrane permeability (IBA). Reason: ANT ligands (CAT, BKA, ADP) modulate permeability transition and ANT-deficient mitochondria need more Ca2+ to open the pore; rat ANT1 overexpression reduces MPTP opening. A genuine but regulatory, non-core role. Supporting Evidence: PMID:14749836 ANTs are non-essential structural components of the mtPTP, although they do contribute to its regulation. PMID:22564366 Heart-specific overexpression of ANT1 leads to a reduced apoptotic response to TGFΞ²(1) by preservation of the mitochondrial membrane potential, resistance to MPTP opening and altered TGFΞ² signaling. |
| GO:0046902 regulation of mitochondrial membrane permeability | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of mitochondrial membrane permeability (ISO). Reason: ANT ligands (CAT, BKA, ADP) modulate permeability transition and ANT-deficient mitochondria need more Ca2+ to open the pore; rat ANT1 overexpression reduces MPTP opening. A genuine but regulatory, non-core role. Supporting Evidence: PMID:14749836 ANTs are non-essential structural components of the mtPTP, although they do contribute to its regulation. PMID:22564366 Heart-specific overexpression of ANT1 leads to a reduced apoptotic response to TGFΞ²(1) by preservation of the mitochondrial membrane potential, resistance to MPTP opening and altered TGFΞ² signaling. |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | MODIFY | Summary: Transmembrane transport (IEA from mitochondrial carrier InterPro signature). Reason: True but general. The specific transmembrane transport processes ANT1 mediates are mitochondrial ADP import and ATP export (both is_a descendants of GO:0055085, checked with OAK, and already carried by other rows). Proposed replacements: mitochondrial ADP transmembrane transport mitochondrial ATP transmembrane transport Supporting Evidence: UniProtKB:Q05962 Belongs to the mitochondrial carrier (TC 2.A.29) family. UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell |
| GO:0060546 negative regulation of necroptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of necroptotic process (ISO from human). Reason: Rests on human data that RIP1-dependent inhibition of ANT ADP/ATP exchange promotes necrosis, i.e. ANT activity restrains necrotic death. Context-dependent and downstream of the core transport; non-core. Supporting Evidence: PMID:16507998 tumor necrosis factor alpha induced RIP-dependent inhibition of adenine nucleotide translocase (ANT)-conducted transport of ADP into mitochondria, which resulted in reduced ATP and necrotic cell death PMID:16507998 the ectopic expression of ANT or cyclophilin D was effective at preventing cell death |
| GO:0061051 positive regulation of cell growth involved in cardiac muscle cell development | IDA PMID:21325829 Transgenic overexpression of heart-specific adenine nucleoti... | MARK AS OVER ANNOTATED | Summary: Positive regulation of cell growth involved in cardiac muscle cell development, from rat ANT1 transgenic cardiomyocytes. Reason: Overexpression of ANT1 in rat heart increased cardiomyocyte volume and myofibrillar protein content. This is an indirect gain-of-function consequence of increased energy supply in adult cells, not evidence that ANT1 regulates developmental cell growth. Abstract only. Supporting Evidence: PMID:21325829 ANT1-TG cardiomyoycytes displayed an elevation in cell volume |
| GO:0070555 response to interleukin-1 | IEP PMID:15950780 Interleukin-1beta induces CREB-binding protein (CBP) mRNA in... | KEEP AS NON CORE | Summary: Ant1 mRNA is upregulated by intraventricular IL-1beta in rat brain. Reason: IEP response term: the expression change is documented, but no role of ANT1 in IL-1 signalling is implied. Retained as non-core. Supporting Evidence: PMID:15950780 both CBP and ANT-1 transcripts were upregulated in the cerebral cortex and hypothalamus |
| GO:0140021 mitochondrial ADP transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: Mitochondrial ADP transmembrane transport (IEA). Reason: ADP import into the matrix in exchange for ATP is the core process of ANT1. Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation |
| GO:0140021 mitochondrial ADP transmembrane transport | ISO GO_REF:0000121 | ACCEPT | Summary: Mitochondrial ADP transmembrane transport (ISO). Reason: ADP import into the matrix in exchange for ATP is the core process of ANT1. Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation |
| GO:0140021 mitochondrial ADP transmembrane transport | ISO GO_REF:0000121 | ACCEPT | Summary: Mitochondrial ADP transmembrane transport (ISO). Reason: ADP import into the matrix in exchange for ATP is the core process of ANT1. Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation |
| GO:0140021 mitochondrial ADP transmembrane transport | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial ADP transmembrane transport (ISS). Reason: ADP import into the matrix in exchange for ATP is the core process of ANT1. Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation |
| GO:1901526 positive regulation of mitophagy | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of mitophagy (ISO). Reason: ANT1 promotes PINK1/parkin mitophagy independently of nucleotide exchange, via TIM44 and TIM23 inhibition; Ant1-null mice show blunted mitophagy. Well supported but a moonlighting, non-core role. Supporting Evidence: PMID:31618756 ANT promotes mitophagy independently of its nucleotide translocase catalytic activity. |
| GO:1901526 positive regulation of mitophagy | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of mitophagy (ISS). Reason: ANT1 promotes PINK1/parkin mitophagy independently of nucleotide exchange, via TIM44 and TIM23 inhibition; Ant1-null mice show blunted mitophagy. Well supported but a moonlighting, non-core role. Supporting Evidence: PMID:31618756 ANT promotes mitophagy independently of its nucleotide translocase catalytic activity. |
| GO:1902109 negative regulation of mitochondrial membrane permeability involved in apoptotic process | IDA PMID:22564366 Transgenic overexpression of the adenine nucleotide transloc... | KEEP AS NON CORE | Summary: ANT1 overexpression reduces MPTP opening in TGFb1-treated rat cardiomyocytes. Reason: Calcein and calcium-retention assays show reduced MPTP open probability with ANT1 overexpression, consistent with ANT modulation of the pore. Regulatory, non-core (abstract only). Supporting Evidence: PMID:22564366 Heart-specific overexpression of ANT1 leads to a reduced apoptotic response to TGFΞ²(1) by preservation of the mitochondrial membrane potential, resistance to MPTP opening and altered TGFΞ² signaling. |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000120 | ACCEPT | Summary: Proton transmembrane transport (IEA, inferred from proton transporter and uncoupler activity annotations). Reason: Follows from the fatty-acid-dependent H+ leak mode of ANT1 established in mouse AAC1 and in rat muscle mitochondria. Supporting Evidence: PMID:31341297 The AAC-mediated H+ current requires free fatty acids and resembles the H+ leak via the thermogenic uncoupling protein 1 found in brown fat. PMID:18251717 an endogenously generated activator stimulates proton conductance catalysed partly by UCP3 and partly by the adenine nucleotide translocase |
| GO:1990544 mitochondrial ATP transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial ATP transmembrane transport (IBA). Reason: Export of matrix ATP to the cytosol in exchange for ADP is the core process of ANT1. Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation UniProtKB:Q05962 Belongs to the mitochondrial carrier (TC 2.A.29) family. |
| GO:1990544 mitochondrial ATP transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: Mitochondrial ATP transmembrane transport (IEA). Reason: Export of matrix ATP to the cytosol in exchange for ADP is the core process of ANT1. Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation UniProtKB:Q05962 Belongs to the mitochondrial carrier (TC 2.A.29) family. |
| GO:1990544 mitochondrial ATP transmembrane transport | ISO GO_REF:0000121 | ACCEPT | Summary: Mitochondrial ATP transmembrane transport (ISO). Reason: Export of matrix ATP to the cytosol in exchange for ADP is the core process of ANT1. Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation |
| GO:1990544 mitochondrial ATP transmembrane transport | ISO GO_REF:0000121 | ACCEPT | Summary: Mitochondrial ATP transmembrane transport (ISO). Reason: Export of matrix ATP to the cytosol in exchange for ADP is the core process of ANT1. Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation |
| GO:1990544 mitochondrial ATP transmembrane transport | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial ATP transmembrane transport (ISS). Reason: Export of matrix ATP to the cytosol in exchange for ADP is the core process of ANT1. Supporting Evidence: UniProtKB:Q05962 ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell PMID:37278158 imports ADP into the mitochondrial matrix and exports ATP, which are key steps in oxidative phosphorylation |
| GO:1990845 adaptive thermogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Adaptive thermogenesis (ISO). Reason: ANT1-mediated H+ leak dissipates the protonmotive force as heat and has been proposed to link ATP demand to thermogenesis, but adaptive thermogenesis as an organismal response is not shown to depend on ANT1 in rat. Non-core. Supporting Evidence: PMID:31341297 By mediating two distinct transport modes, ADP/ATP exchange and H+ leak, AAC connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria. |
| GO:1990845 adaptive thermogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Adaptive thermogenesis (ISS). Reason: ANT1-mediated H+ leak dissipates the protonmotive force as heat and has been proposed to link ATP demand to thermogenesis, but adaptive thermogenesis as an organismal response is not shown to depend on ANT1 in rat. Non-core. Supporting Evidence: PMID:31341297 By mediating two distinct transport modes, ADP/ATP exchange and H+ leak, AAC connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria. |
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Download this section (compressed HTML)Q: Is ANT1 a pore-forming component of the mitochondrial permeability transition pore or only a regulator of it, and do ANT1 and ANT2 differ in this role in rat heart?
Q: How much of the carboxyatractylate-sensitive proton leak in rat heart and skeletal muscle is carried by ANT1 rather than ANT2, and how is it regulated in vivo?
Q: Did the rat raft proteomics (PMID:14499952) and liver IMM pull-down (PMID:9820802) detect ANT1 specifically or a pan-ANT signal? Isoform-specific reagents would settle which rat experimental rows belong to Slc25a4 rather than Slc25a5.
Experiment: Patch-clamp inner membranes from Slc25a4-knockout and wild-type rat cardiomyocytes to quantify ANT1-specific fatty-acid-dependent H+ current versus ADP/ATP exchange current.
Experiment: Use isoform-specific antibodies or tagged knock-in rats to test whether ANT1 is present in detergent-resistant plasma-membrane fractions or only in mitochondrial inner membrane.
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