SLC25A24 (SCaMC-1 / APC1) is a calcium-regulated mitochondrial ATP-Mg/phosphate carrier of the SLC25 mitochondrial carrier family. It is a multi-pass protein of the mitochondrial inner membrane that catalyzes the electroneutral antiport of cytosolic adenine nucleotides (principally ATP-Mg, but also ADP and AMP) for matrix inorganic phosphate, thereby setting the size of the mitochondrial matrix adenine-nucleotide pool and adapting it to changing cellular energetic demand. The protein has a bipartite architecture: a C-terminal six-transmembrane mitochondrial-carrier (transporter) domain, and an N-terminal regulatory domain bearing four EF-hand calcium-binding motifs that faces the intermembrane space. Transport is switched on by a rise in cytosolic calcium: calcium binding to the EF-hand domain triggers a conformational change that uncaps the carrier domain, whereas in the calcium-free state the N-terminal domain caps and inhibits the transporter. By importing ATP/ADP into the matrix following a calcium signal, SLC25A24 contributes to matrix calcium buffering, desensitization of the mitochondrial permeability transition, and protection against oxidative-stress- induced cell death. Dominant de novo missense variants at Arg217 cause Fontaine progeroid syndrome (Gorlin-Chaudhry-Moss syndrome), a growth-retardation and progeroid disorder with craniosynostosis and mitochondrial dysfunction.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) inference of mitochondrial localization. Correct but less specific than the mitochondrial inner membrane assignment and redundant with multiple experimental mitochondrion annotations. Reason: Localization to mitochondrion is well supported experimentally, but for the core representation the more specific mitochondrial inner membrane term is preferred. Supporting Evidence: file:human/SLC25A24/SLC25A24-uniprot.txt Mitochondrion inner membrane |
| GO:0015866 ADP transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of ADP transport. Consistent with the carrier's measured ADP/phosphate antiport activity, though the physiologically salient cargo is ATP-Mg. Supporting Evidence: PMID:15123600 the three isoforms of the ATP-Mg/Pi carrier are most likely responsible for the net uptake or efflux of adenine nucleotides into or from the mitochondria |
| GO:1990544 mitochondrial ATP transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of mitochondrial ATP transmembrane transport, matching the experimentally demonstrated core process of this carrier. Supporting Evidence: PMID:15123600 ATP-Mg is transported in exchange for phosphate |
| GO:0140988 ADP:phosphate antiporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of ADP:phosphate antiporter activity, consistent with the experimentally measured ADP/Pi antiport (IDA from PMID:15123600). Supporting Evidence: PMID:15123600 ATP-Mg is transported in exchange for phosphate |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro (EF-hand) electronic inference of calcium ion binding. Correct: the N-terminal regulatory domain contains four calcium-binding EF-hands, directly demonstrated structurally. Supporting Evidence: file:human/SLC25A24/SLC25A24-uniprot.txt The regulatory N-terminal domain/NTD, formed of two pairs of |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniProtKB-SubCell) inference of mitochondrial inner membrane localization. This is the correct, specific location for this multi-pass mitochondrial carrier and is the preferred core location term. Supporting Evidence: file:human/SLC25A24/SLC25A24-uniprot.txt Mitochondrion inner membrane |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro electronic inference of transmembrane transport. Correct but a very general parent of the specific mitochondrial ATP/adenine-nucleotide transmembrane transport that this carrier performs. Reason: True but uninformative; the specific transport processes (mitochondrial ATP transmembrane transport, adenine nucleotide transport) capture the core function. |
| GO:0140987 ATP:phosphate antiporter activity | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic inference of ATP:phosphate antiporter activity, redundant with and confirmed by the experimental IDA annotation to the same term from PMID:15123600. Supporting Evidence: file:human/SLC25A24/SLC25A24-uniprot.txt Reaction=phosphate(in) + ATP(out) + 2 H(+)(out) = phosphate(out) + |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic inference of mitochondrial localization. Correct but redundant with the more specific inner-membrane term and with experimental mitochondrion annotations. Reason: Redundant, less-specific parent of mitochondrial inner membrane. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Immunofluorescence (HPA) evidence of mitochondrial localization. Correct and experimentally supported, but less specific than mitochondrial inner membrane. Reason: Consistent experimental localization; subsumed by the inner-membrane core term. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput mitochondrial proteome evidence of mitochondrial localization. Correct; corroborates mitochondrial residence but is less specific than the inner membrane and redundant with experimental annotations. Reason: Redundant, less-specific parent of mitochondrial inner membrane. |
| GO:0000295 adenine nucleotide transmembrane transporter activity | IDA PMID:15123600 Identification of the mitochondrial ATP-Mg/Pi transporter. B... | ACCEPT | Summary: Direct assay (reconstitution of the bacterially expressed carrier into liposomes) demonstrates broad-specificity adenine nucleotide transmembrane transport (AMP, ADP, ATP, ATP-Mg). A well-supported core molecular function. Supporting Evidence: PMID:15123600 the three isoforms of the ATP-Mg/Pi carrier are most likely responsible for the net uptake or efflux of adenine nucleotides into or from the mitochondria |
| GO:0140988 ADP:phosphate antiporter activity | IDA PMID:15123600 Identification of the mitochondrial ATP-Mg/Pi transporter. B... | ACCEPT | Summary: Direct assay of the reconstituted carrier demonstrates ADP/inorganic-phosphate antiport. A core molecular function capturing the specific electroneutral antiport mechanism. Supporting Evidence: file:human/SLC25A24/SLC25A24-uniprot.txt Reaction=ADP(out) + phosphate(in) + H(+)(out) = ADP(in) + |
| GO:1990544 mitochondrial ATP transmembrane transport | IDA PMID:15123600 Identification of the mitochondrial ATP-Mg/Pi transporter. B... | ACCEPT | Summary: Direct demonstration of ATP-Mg/phosphate antiport across the inner mitochondrial membrane by the reconstituted carrier. The core biological process. Supporting Evidence: PMID:15123600 ATP-Mg is transported in exchange for phosphate |
| GO:0005347 ATP transmembrane transporter activity | IMP PMID:22015608 SCaMC-1 promotes cancer cell survival by desensitizing mitoc... | ACCEPT | Summary: Loss/gain-of-function (knockdown/overexpression) evidence that SLC25A24 mediates calcium-dependent ATP-Mg/ADP uptake into mitochondria, establishing ATP transmembrane transporter activity. This is the best single term for the core molecular function (the physiologically salient cargo is ATP). Supporting Evidence: PMID:22015608 the mitochondrial carrier SCaMC-1/SLC25A24 mediates ATP-Mg(2-)/Pi(2-) and/or HADP(2-)/Pi(2-) uptake into the mitochondria after an increase in cytosolic |
| GO:1990544 mitochondrial ATP transmembrane transport | IMP PMID:22015608 SCaMC-1 promotes cancer cell survival by desensitizing mitoc... | ACCEPT | Summary: Independent (IMP) support for calcium-triggered mitochondrial ATP transmembrane transport by SLC25A24. Consistent with the IDA annotation to the same term. Supporting Evidence: PMID:22015608 mediates ATP-Mg(2-)/Pi(2-) and/or HADP(2-)/Pi(2-) uptake into the mitochondria after an increase in cytosolic |
| GO:0140987 ATP:phosphate antiporter activity | IDA PMID:15123600 Identification of the mitochondrial ATP-Mg/Pi transporter. B... | ACCEPT | Summary: Direct assay of the reconstituted carrier demonstrates ATP/inorganic-phosphate antiport. Core molecular function capturing the specific antiport mechanism (matches the ATP-Mg/Pi and ATP/Pi exchange reactions). Supporting Evidence: file:human/SLC25A24/SLC25A24-uniprot.txt Reaction=Mg(2+)(out) + phosphate(in) + ATP(out) = Mg(2+)(in) + |
| GO:0005509 calcium ion binding | EXP PMID:24332718 A self-sequestered calmodulin-like Ca²⁺ sensor of mitochondr... | ACCEPT | Summary: Experimental (crystallography/NMR) demonstration that the N-terminal EF-hand domain binds calcium. Genuine secondary molecular function underlying calcium regulation of transport. Supporting Evidence: PMID:24332718 Crystal structure of the Ca²⁺-bound NTD reveals a compact architecture in which the functional EF hands are sequestered by an endogenous helical segment |
| GO:0005739 mitochondrion | IDA PMID:15123600 Identification of the mitochondrial ATP-Mg/Pi transporter. B... | KEEP AS NON CORE | Summary: Direct (targeting/localization) evidence of mitochondrial residence. Correct but less specific than the mitochondrial inner membrane core location. Reason: Subsumed by mitochondrial inner membrane. Supporting Evidence: PMID:15123600 their targeting to mitochondria |
| GO:0051503 adenine nucleotide transport | IDA PMID:15123600 Identification of the mitochondrial ATP-Mg/Pi transporter. B... | ACCEPT | Summary: Direct assay evidence of adenine nucleotide transport. A core biological process capturing the broad adenine-nucleotide (AMP/ADP/ATP) cargo range of the carrier. Supporting Evidence: PMID:15123600 the net uptake or efflux of adenine nucleotides into or from the mitochondria |
| GO:0005739 mitochondrion | IDA PMID:15054102 Identification of a novel human subfamily of mitochondrial c... | KEEP AS NON CORE | Summary: Direct evidence (SCaMC subfamily characterization) that the protein localizes exclusively to mitochondria. Correct but less specific than inner membrane. Reason: Subsumed by mitochondrial inner membrane. Supporting Evidence: PMID:15054102 All SCaMC proteins were found to be located exclusively in mitochondria |
| GO:0005739 mitochondrion | IDA PMID:29100093 De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndr... | KEEP AS NON CORE | Summary: Direct evidence that mutant SLC25A24 retains normal mitochondrial localization in patient fibroblasts. Confirms mitochondrial residence; less specific than inner membrane. Reason: Subsumed by mitochondrial inner membrane. |
| GO:0006839 mitochondrial transport | IMP PMID:29100093 De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndr... | KEEP AS NON CORE | Summary: Patient-variant (IMP) evidence of altered mitochondrial (ATP) transport. Correct but a general parent of the specific mitochondrial ATP transmembrane transport term. Reason: True but subsumed by the more specific mitochondrial ATP transmembrane transport (GO:1990544) that captures the core process. |
| GO:0034599 cellular response to oxidative stress | IMP PMID:29100093 De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndr... | KEEP AS NON CORE | Summary: Patient-variant (IMP) evidence linking SLC25A24 to protection against oxidative stress: mutant fibroblasts show mitochondrial swelling exacerbated by H2O2 and increased sensitivity to oxidative stress. A physiological/disease-relevant role downstream of the transport activity, not the carrier's core molecular function. Supporting Evidence: PMID:29100093 mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations |
| GO:0005509 calcium ion binding | IDA PMID:24332718 A self-sequestered calmodulin-like Ca²⁺ sensor of mitochondr... | ACCEPT | Summary: Direct (structural) evidence of calcium binding by the EF-hand N-terminal domain. Genuine secondary molecular function; duplicate of the EXP annotation to the same term from the same paper. Supporting Evidence: PMID:24332718 Crystal structure of the Ca²⁺-bound NTD reveals a compact architecture in which the functional EF hands are sequestered by an endogenous helical segment |
| GO:0005739 mitochondrion | IDA PMID:22015608 SCaMC-1 promotes cancer cell survival by desensitizing mitoc... | KEEP AS NON CORE | Summary: Direct evidence of mitochondrial localization from the SCaMC-1 functional study. Correct but less specific than the mitochondrial inner membrane core location. Reason: Subsumed by mitochondrial inner membrane. |
| GO:0016020 membrane | IDA PMID:24332718 A self-sequestered calmodulin-like Ca²⁺ sensor of mitochondr... | MARK AS OVER ANNOTATED | Summary: Generic membrane localization. Uninformative parent term; SLC25A24 is a multi-pass protein of the mitochondrial inner membrane, so the specific inner-membrane term should be used instead. Reason: GO:0016020 membrane is an uninformative high-level term; mitochondrial inner membrane (GO:0005743) is the appropriate specific location. |
| GO:0071277 cellular response to calcium ion | IMP PMID:22015608 SCaMC-1 promotes cancer cell survival by desensitizing mitoc... | KEEP AS NON CORE | Summary: Evidence that SLC25A24 transport activity is triggered by, and responds to, a rise in cytosolic calcium (calcium-dependent ATP-Mg/ADP uptake and matrix calcium buffering). A downstream/regulatory process rather than the core transporter function. Supporting Evidence: PMID:22015608 uptake into the mitochondria after an increase in cytosolic [Ca(2+)] |
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