SLC25A12 (Aralar / AGC1) — gene review notes

Identity

UniProt: O75746 (S2512_HUMAN); HGNC:10982; gene SLC25A12; 678 aa.
RecName: "Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial";
AltName: Aralar / Aralar1; Mitochondrial aspartate glutamate carrier 1 (AGC1);
synonyms AGC1, ARALAR1 [file:human/SLC25A12/SLC25A12-uniprot.txt lines 6-14].
Member of the mitochondrial carrier (SLC25 / TC 2.A.29) family
[file:human/SLC25A12/SLC25A12-uniprot.txt "Belongs to the mitochondrial carrier (TC 2.A.29) family."].
Paralog: SLC25A13 / citrin / AGC2 (Q9UJS0), the non-excitable-tissue isoform; 77% identical
PMID:25410934.

Mitochondrial electrogenic aspartate/glutamate antiporter: exports L-aspartate from the matrix
in exchange for cytosolic L-glutamate + H+
[file:human/SLC25A12/SLC25A12-uniprot.txt "that favors efflux of aspartate and entry of glutamate and proton"].
Rhea reaction (UniProt CATALYTIC ACTIVITY): L-aspartate(in) + L-glutamate(out) + H(+)(out) =
L-aspartate(out) + L-glutamate(in) + H(+)(in); RHEA:70783
[file:human/SLC25A12/SLC25A12-uniprot.txt lines 221-226].
Reconstituted-liposome proof of transport function (recombinant human aralar1 + citrin):
PMID:11566871.
Overexpression in HEK-293T cells raised shuttle activity
PMID:11566871.
Ca2+ stimulation from the external (IMS) face of the inner membrane
[PMID:11566871 "was stimulated by Ca 2+ on the external side of"; and file:...-uniprot.txt
"ACTIVITY REGULATION: Activated by calcium-binding in the mitochondrial"].
Also transports L-cysteinesulfinate in exchange for glutamate or aspartate
PMID:11566871.
This underlies the GO:0000514 (3-sulfino-L-alanine:proton,glutamate antiporter) annotation (IDA PMID:11566871).
Does NOT transport GABA (negative finding, corrects a Drosophila claim) and does not transport
L-glutamine [PMID:38945283 "AGC does not transport GABA"; "GABA has no inhibitory effect on the";
file:...-uniprot.txt "Lacks transport activity towards L-glutamine or ... GABA"].

GO:0000515 "aspartate:glutamate, proton antiporter activity" (MF) is the most specific term and
matches the Rhea reaction exactly. Confirmed in go.db to be a descendant of GO:0015183
(L-aspartate transmembrane transporter activity), GO:0005313 (L-glutamate transmembrane transporter
activity), GO:0015297 (antiporter activity), and GO:0015078 (proton transmembrane transporter
activity). Strong experimental support: IDA PMID:11566871, EXP PMID:19641205, EXP/IDA PMID:24515575,
EXP PMID:38945283. This is the primary core function.
GO:0000514 "3-sulfino-L-alanine: proton, glutamate antiporter activity" (MF, IDA PMID:11566871) is
a genuine secondary catalytic-transport activity (cysteinesulfinate carrier).
The IBA terms GO:0015183 and GO:0005313 are correct but less specific parents of GO:0000515.

N-terminal regulatory domain (residues 2-294) has EF-hand motifs; binds Ca2+ in the IMS to gate the
carrier [file:...-uniprot.txt "Regulatory N-terminal domain"; "binds one calcium in the mitochondrial
intermembrane space. Calcium"].
Crystal structures (4P5X/4P60): homodimer; of 8 EF-hands only EF-hand 2 binds Ca2+; EF-hands 4-8 form
a static dimerization interface [PMID:25410934 "Only EF-hand 2 binds calcium"; "form a twofold
symmetrical homodimer"; "import glutamate together with a proton into the mitochondrial matrix and
export aspartate"].
GO:0005509 calcium ion binding is well supported experimentally (IDA PMID:9722566, IDA PMID:25410934).
GO:0042802 identical protein binding (IDA PMID:25410934) captures the homodimer (SUBUNIT: "Homodimer
(via N-terminus)").

Makes the malate-aspartate shuttle directional/irreversible; transfers reducing equivalents (NADH)
into mitochondria [PMID:19641205 "supplies aspartate to the cytosol and, as a component of the";
"malate-aspartate shuttle, enables mitochondrial oxidation of cytosolic NADH"; PMID:24515575 "an
essential component of the" neuronal malate/aspartate shuttle that "transfers NADH and H(+) reducing"
equivalents]. GO:0043490 malate-aspartate shuttle (IDA PMID:11566871; IGI PMID:37647199).
Downstream transport processes: GO:0015810 aspartate transmembrane transport, GO:0015813 L-glutamate
transmembrane transport (both IDA PMID:11566871/19641205/24515575) — components of the antiport.
Ca2+ regulation captured by GO:0051592 response to calcium ion (IDA PMID:11566871).

Mitochondrion inner membrane, multi-pass; N- and C-terminal domains face the intermembrane space
[file:...-uniprot.txt "SUBCELLULAR LOCATION: Mitochondrion inner membrane"]. GO:0005743 mitochondrial
inner membrane (IDA PMID:11566871; EXP PMID:9722566/19641205/24515575; TAS Reactome). GO:0005739
mitochondrion (IDA/HDA/HTP) is the correct but less specific parent.

Predominantly heart and skeletal muscle, weaker in brain/kidney; neuron- and muscle-specific isoform
[file:...-uniprot.txt "Expressed predominantly in the heart and skeletal muscle, weakly in brain and kidney"].
Biallelic loss-of-function causes Developmental and epileptic encephalopathy 39 with leukodystrophy
(DEE39; MIM:612949) — global cerebral hypomyelination, epilepsy, reduced N-acetylaspartate. Variants
Q590R and R353Q abolish/reduce antiporter activity [PMID:19641205 "showed abolished activity";
PMID:24515575 "AGC1 activity was reduced to 15% of" wild type]. Neuronal aspartate efflux is required
for NAA production and myelination.

GO:0005515 protein binding IPIs: with SLC25A13/citrin (Q9UJS0; PMID:28514442 BioPlex, PMID:33961781,
PMID:40355756 SLC superfamily interactome) and with MAVS (Q7Z434; PMID:31767682). These are generic
"protein binding" (uninformative MF); the citrin ones are consistent with the shared SLC25 biology and
the UniProt IntAct records (O75746–Q9UJS0, O75746–Q7Z434). Per policy, bare protein binding IPIs are
marked MARK_AS_OVER_ANNOTATED (not removed); the homodimer is better captured by GO:0042802.
PMID:31767682: SLC25A12, as part of a prohibitin complex, associates with MAVS and links mitochondrial
metabolism to antiviral innate immunity PMID:31767682. This is a regulatory/context finding, not a core MF.

ACCEPT (core): GO:0000515 antiporter MF (all IDA/EXP), GO:0043490 malate-aspartate shuttle (IDA/IGI),
GO:0005743 mito inner membrane (IDA/EXP), GO:0005509 calcium ion binding (IDA).
ACCEPT (non-core but correct/experimental): GO:0000514 cysteinesulfinate antiporter (IDA), GO:0015810,
GO:0015813 (IDA transport processes), GO:0051592 response to calcium (IDA), GO:0042802 identical
protein binding (IDA, homodimer), GO:0005739 mitochondrion (IDA/HDA/HTP), GO:0016020 membrane (NAS,
less specific parent).
IBA (phylogenetic) annotations to transporter MF/BP and inner membrane: ACCEPT (consistent with
experimental data), though GO:0015183/GO:0005313 are less specific than GO:0000515.
IEA: mostly ACCEPT as correct-but-redundant (ARBA duplicates of experimental terms; SubCell inner
membrane; InterPro transmembrane transport). GO:0015804 "neutral amino acid transport" (GOC inference
from the cysteinesulfinate term) and GO:1902600 "proton transmembrane transport" (GOC) are marked
over-annotated / kept as non-core — aspartate and glutamate are acidic amino acids, and the proton is
co-transported as part of the antiport rather than representing a standalone proton-transport function.
Protein binding IPIs (GO:0005515 x4): MARK_AS_OVER_ANNOTATED (uninformative bare MF), never removed.