SLC25A24 (SCaMC-1 / APC1) — review notes

UniProt: Q6NUK1 (SCMC1_HUMAN). HGNC:20662. 477 aa. Human, NCBITaxon:9606.

Identity / naming

• RecName: "Mitochondrial adenyl nucleotide antiporter SLC25A24" [file:human/SLC25A24/SLC25A24-uniprot.txt "RecName: Full=Mitochondrial adenyl nucleotide antiporter SLC25A24"].
• AltName: "Mitochondrial ATP-Mg/Pi carrier protein 1" (APC1); "Short calcium-binding mitochondrial carrier protein 1" / SCaMC-1 [file:human/SLC25A24/SLC25A24-uniprot.txt "Short=SCaMC-1"].
• Synonyms: APC1, MCSC1, SCAMC1 [file:human/SLC25A24/SLC25A24-uniprot.txt "Synonyms=APC1"].
• Member of the mitochondrial carrier (TC 2.A.29) family, SLC25 [file:human/SLC25A24/SLC25A24-uniprot.txt "Belongs to the mitochondrial carrier (TC 2.A.29) family"].

Core molecular function — a Ca2+-regulated ATP-Mg/Pi (adenine nucleotide) antiporter

• FUNCTION: "Electroneutral antiporter that mediates the transport of adenyl nucleotides through the inner mitochondrial membrane. Originally identified as an ATP-magnesium/inorganic phosphate antiporter, it also acts as a broad specificity adenyl nucleotide antiporter. By regulating the mitochondrial matrix adenyl nucleotide pool, could adapt to changing cellular energetic demands and indirectly regulate adenyl nucleotide-dependent metabolic pathways" [file:human/SLC25A24/SLC25A24-uniprot.txt].
• In vitro also low activity with guanyl and pyrimidine nucleotides [file:human/SLC25A24/SLC25A24-uniprot.txt "In vitro, a low activity is also observed with guanyl and pyrimidine nucleotides"].
• This is a TRANSPORTER, not an enzyme — no catalytic (EC/enzymatic) MF should be assigned. The UniProt "CATALYTIC ACTIVITY" Rhea reactions are antiport half-reactions (e.g. RHEA:65840 Mg/Pi + ATP exchange), i.e. transport, not chemistry.
• PMID:15123600 (Fiermonte et al 2004): purified/reconstituted the human ATP-Mg/Pi carrier; measured KM/Vmax for AMP, ADP, ATP, ATP-Mg, Pi antiport. Abstract: "ATP-Mg is transported in exchange for phosphate... 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 and hence for the variation in the matrix adenine nucleotide content" PMID:15123600. This is the primary IDA source for the MF transporter terms (adenine nucleotide transmembrane transporter GO:0000295, ATP:phosphate antiporter GO:0140987, ADP:phosphate antiporter GO:0140988) and BP (mitochondrial ATP transmembrane transport GO:1990544, adenine nucleotide transport GO:0051503).
• PMID:22015608 (Traba et al 2012): "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 [Ca(2+)]" PMID:22015608. Basis for GO:0005347 ATP transmembrane transporter activity (IMP) and GO:1990544 (IMP).

Best-supported core MF: GO:0005347 ATP transmembrane transporter activity (transport of ATP, the physiologically salient cargo; supported by both Fiermonte reconstitution and Traba cellular assays). The paired antiporter/phosphate terms (GO:0140987 ATP:phosphate antiporter, GO:0140988 ADP:phosphate antiporter) and adenine-nucleotide-transporter GO:0000295 capture the specific electroneutral antiport mechanism and broader substrate range; all are consistent. GO:0005509 calcium ion binding is a genuine secondary MF (regulatory EF-hands).

Calcium regulation (secondary MF: Ca2+ binding via EF-hands)

• N-terminal regulatory domain (residues 1–173) with four EF-hands facing the intermembrane space; binds Ca2+; regulates the C-terminal carrier/transmembrane domain [file:human/SLC25A24/SLC25A24-uniprot.txt "The regulatory N-terminal domain/NTD, formed of two pairs of fused calcium-binding EF-hands, binds calcium in the mitochondrial intermembrane space"].
• Activated by a rise in cytosolic Ca2+ that induces a conformational change uncapping the channel [file:human/SLC25A24/SLC25A24-uniprot.txt "Activated by an increase in cytosolic calcium levels that induces a conformational change of the N-terminal regulatory domain, uncapping the channel and allowing transport"].
• PMID:24332718 (Yang, Brüschweiler, Chou 2014): crystal structure (2.1 Å; PDB 4N5X) of the Ca2+-bound NTD (residues 1–193); NMR + SPR. Ca2+ binding drives a conformational switch: apo NTD caps/binds TMD (inhibits transport); Ca2+-bound NTD is self-sequestered and releases TMD. Abstract: "The short Ca²⁺-binding mitochondrial carrier (SCaMC) transports ATP-Mg in exchange for Pi... Crystal structure of the Ca²⁺-bound NTD reveals a compact architecture in which the functional EF hands are sequestered by an endogenous helical segment... Ca²⁺ binding drastically weakened the interaction. Our results together provide a molecular explanation for Ca²⁺-dependent ATP-Mg flux in mitochondria" PMID:24332718. Primary IDA/EXP source for GO:0005509 calcium ion binding and for GO:0071277-type Ca2+ responsiveness.
• Additional structural support (not in GOA/local pubs): PMID:26164100 (Harborne et al 2015, PDB 4ZCU/4ZCV), PMID:28350015 (Harborne et al 2017, locking-pin mechanism) — cited in UniProt but not in the review set.

Localization

• SUBCELLULAR LOCATION: "Mitochondrion inner membrane ... Multi-pass membrane protein" [file:human/SLC25A24/SLC25A24-uniprot.txt "Mitochondrion inner membrane"]. Six TM helices (TRANSMEM 198–465 region); N-terminal EF-hand domain in the intermembrane space.
• IDA localization to mitochondrion from PMID:15123600, PMID:15054102, PMID:22015608, PMID:29100093 (all human SLC25A24). PMID:15054102 (del Arco & Satrústegui 2004): "All SCaMC proteins were found to be located exclusively in mitochondria" PMID:15054102.
• GO:0016020 membrane (IDA, PMID:24332718) is a less-informative parent of mitochondrial inner membrane — over-annotation given inner-membrane evidence.
• Core location term: GO:0005743 mitochondrial inner membrane (IEA UniProtKB-SubCell, consistent with the multi-pass carrier + literature).

Biological process / physiology / disease

• Regulates the mitochondrial matrix adenine nucleotide pool → adapts to energetic demand; supports adenine-nucleotide-dependent processes (gluconeogenesis, mitochondrial biogenesis, mtDNA maintenance per PMID:24332718 full text).
• Ca2+-dependent matrix Ca2+ buffering via ATP/ADP: PMID:22015608 — SCaMC-1 imports ATP-Mg/ADP after cytosolic Ca2+ rise; ATP/ADP buffer matrix Ca2+, desensitizing mitochondrial permeability transition (mPT); knockdown sensitizes cells to mPT-mediated necrotic death by oxidative stress and Ca2+ overload PMID:22015608. Supports GO:0071277 cellular response to calcium ion (IMP).
• Oxidative stress protection: PMID:29100093 — patient fibroblasts with R217H/R217C show mitochondrial swelling exacerbated by H2O2, lower matrix ATP, increased sensitivity to oxidative stress PMID:29100093. Supports GO:0034599 cellular response to oxidative stress (IMP) and GO:0006839 mitochondrial transport (IMP; the assayed defect is altered mitochondrial ATP transport).
• DISEASE: Fontaine progeroid syndrome (FPS) [MIM:612289] = Gorlin-Chaudhry-Moss syndrome; autosomal dominant, de novo recurrent p.Arg217His / p.Arg217Cys; gain-of-pathological-function [file:human/SLC25A24/SLC25A24-uniprot.txt "Fontaine progeroid syndrome (FPS)"] PMID:29100093.

Annotation-by-annotation decisions (summary)

MF:
- GO:0005347 ATP transmembrane transporter activity (IMP, PMID:22015608): ACCEPT — core.
- GO:0000295 adenine nucleotide transmembrane transporter activity (IDA, PMID:15123600): ACCEPT — core (broad-specificity adenine nucleotide antiport).
- GO:0140987 ATP:phosphate antiporter activity (IDA, PMID:15123600): ACCEPT — core (specific mechanism; matches Rhea reactions in UniProt).
- GO:0140988 ADP:phosphate antiporter activity (IDA, PMID:15123600): ACCEPT — core (ADP/Pi antiport measured).
- GO:0140987 ATP:phosphate antiporter (IEA, GO_REF:0000117 ARBA): ACCEPT (redundant with IDA; keep).
- GO:0140988 ADP:phosphate antiporter (IBA, GO_REF:0000033): ACCEPT (phylogenetic, consistent).
- GO:0005509 calcium ion binding (IDA PMID:24332718; EXP PMID:24332718; IEA InterPro): ACCEPT — genuine secondary MF (EF-hands).

BP:
- GO:1990544 mitochondrial ATP transmembrane transport (IDA PMID:15123600; IMP PMID:22015608; IBA): ACCEPT — core.
- GO:0051503 adenine nucleotide transport (IDA PMID:15123600): ACCEPT — core (broader parent BP).
- GO:0015866 ADP transport (IBA GO_REF:0000033): ACCEPT / KEEP — consistent.
- GO:0071277 cellular response to calcium ion (IMP PMID:22015608): KEEP_AS_NON_CORE — downstream Ca2+-triggered activation, not the transporter's own core function.
- GO:0034599 cellular response to oxidative stress (IMP PMID:29100093): KEEP_AS_NON_CORE — physiological/disease phenotype.
- GO:0006839 mitochondrial transport (IMP PMID:29100093): KEEP_AS_NON_CORE — correct but a general parent of the specific ATP transport term.
- GO:0055085 transmembrane transport (IEA GO_REF:0000002 InterPro): KEEP_AS_NON_CORE — correct but very general (root-ish transport term).

CC:
- GO:0005743 mitochondrial inner membrane (IEA UniProtKB-SubCell): ACCEPT — core location.
- GO:0005739 mitochondrion (multiple IDA PMID:15123600/15054102/22015608/29100093; IBA; IEA; IDA HPA; HTP PMID:34800366): ACCEPT one representative as location; the rest KEEP_AS_NON_CORE (redundant with, and less specific than, inner membrane).
- GO:0016020 membrane (IDA PMID:24332718): MARK_AS_OVER_ANNOTATED — uninformative parent; the paper localizes/works on the mitochondrial inner-membrane carrier.

No annotation warrants REMOVE. IEA terms present are biologically correct (transporter/calcium/mitochondrion), so none is "clearly-wrong IEA."