SLC25A22

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005313 L-glutamate transmembrane transporter activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) call for the substrate-specific transporter activity. This is the correct, core molecular function of GC-1 and is independently supported experimentally (PMID:11897791, IDA). Accept. Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt Mitochondrial glutamate/H(+) symporter. Responsible for the
GO:0015183 L-aspartate transmembrane transporter activity	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Over-annotation. GC-1 is a glutamate-specific glutamate/H+ symporter; the demonstrated activity is glutamate transport, not aspartate transport. This aspartate MF is propagated by phylogenetic inference across the broader mitochondrial-carrier / aspartate-glutamate-carrier clade. Aspartate transport belongs to the aspartate-glutamate carriers (SLC25A12/SLC25A13), not to the glutamate carriers. Neither UniProt FUNCTION nor the primary paper attributes aspartate transport to SLC25A22. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000640306 · Mitochondrial 2-oxodicarboxylate/glutamate carrier clade SUPPORTS SOURCE BUT NOT TARGET The PANTHER clade mixes glutamate carriers (SLC25A22/SLC25A18) with aspartate-glutamate carriers; aspartate transporter activity is a divergent function of the AGC members, not of GC1, which is a glutamate-specific glutamate/H+ symporter. Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt AltName: Full=Glutamate/H(+) symporter 1;
GO:0043490 malate-aspartate shuttle	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: GC-1 contributes to the malate-aspartate shuttle by carrying the glutamate/H+ import leg (glutamate is coimported with a proton and transaminated back in the matrix). This is a valid downstream pathway context but not the core molecular function, which is glutamate/H+ symport. Keep as non-core. Supporting Evidence: Reactome:R-HSA-9856872 which subsequently gets coimported with a proton and transaminated back
GO:0005743 mitochondrial inner membrane	IBA GO_REF:0000033	ACCEPT	Summary: Correct, core cellular location. GC-1 is a multi-pass protein of the mitochondrial inner membrane; supported by UniProt and by direct experimental evidence (PMID:11897791, IDA). Accept. Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane
GO:0015810 aspartate transmembrane transport	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Over-annotation, mirroring the aspartate MF (GO:0015183). GC-1 does not transport aspartate; the process is propagated phylogenetically from aspartate-glutamate carriers. Mark as over-annotated. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000640306 · Mitochondrial 2-oxodicarboxylate/glutamate carrier clade SUPPORTS SOURCE BUT NOT TARGET Aspartate transmembrane transport is a divergent function of the aspartate-glutamate carriers in the clade, not of the glutamate-specific GC1 (SLC25A22). Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt transport of glutamate from the cytosol into the mitochondrial matrix
GO:0015813 L-glutamate transmembrane transport	IBA GO_REF:0000033	ACCEPT	Summary: Correct, core biological process. GC-1 mediates L-glutamate transmembrane transport across the mitochondrial inner membrane; also supported experimentally (PMID:11897791, IDA). Accept. Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt transport of glutamate from the cytosol into the mitochondrial matrix
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000120	ACCEPT	Summary: Automated (IEA) restatement of the core mitochondrial inner-membrane location, consistent with UniProt and experimental evidence. Accept. Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane
GO:0055085 transmembrane transport	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Correct but generic InterPro-derived transmembrane-transport term. Subsumed by the specific glutamate transport annotations. Keep as non-core. Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt Belongs to the mitochondrial carrier (TC 2.A.29) family.
GO:0070778 L-aspartate transmembrane transport	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	Summary: Over-annotation. Inter-ontology inference from the (also over-annotated) aspartate transporter MF GO:0015183. GC-1 is glutamate-specific and does not transport aspartate. Mark as over-annotated. Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt AltName: Full=Glutamate/H(+) symporter 1;
GO:1902600 proton transmembrane transport	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: Mechanistically valid: GC-1 co-transports a proton with each glutamate (electroneutral H+/glutamate symport), so a proton is translocated across the inner membrane. Inferred from the amino acid:proton symporter activity. Keep as a non-core mechanistic component of the core glutamate/H+ symport. Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt Reaction=L-glutamate(in) + H(+)(in) = L-glutamate(out) + H(+)(out);
GO:0005313 L-glutamate transmembrane transporter activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated (IEA) restatement of the core substrate-specific transporter activity; redundant with the IBA and IDA calls for the same term. Accept. Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt Mitochondrial glutamate/H(+) symporter. Responsible for the
GO:0015813 L-glutamate transmembrane transport	IEA GO_REF:0000107	ACCEPT	Summary: Automated (IEA) restatement of the core L-glutamate transmembrane transport process; redundant with the IBA and IDA calls. Accept. Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt transport of glutamate from the cytosol into the mitochondrial matrix
GO:0050796 regulation of insulin secretion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Physiological role assigned by similarity (to rat ortholog); GC-1 is highly expressed in pancreas and UniProt notes a role in glucose-stimulated insulin secretion. This is a downstream/contextual physiological role rather than the core transport function. Keep as non-core. Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt Plays a role
GO:0006836 neurotransmitter transport	TAS Reactome:R-HSA-442660	MARK AS OVER ANNOTATED	Summary: Over-annotation. The cited Reactome node (R-HSA-442660) describes the SLC6 family of plasma-membrane neurotransmitter transporters that terminate synaptic signaling, a distinct process from SLC25A22's mitochondrial inner-membrane glutamate/H+ symport. GC-1 handles glutamate as a mitochondrial metabolite, not as a synaptic neurotransmitter being cleared from the cleft. Mark as over-annotated. Supporting Evidence: Reactome:R-HSA-442660 The SLC6 gene family encodes proteins that mediate neurotransmitter uptake
GO:0043490 malate-aspartate shuttle	TAS Reactome:R-HSA-9856872	KEEP AS NON CORE	Summary: Reactome-asserted participation in the malate-aspartate shuttle via the glutamate/H+ import leg. Valid pathway context but not the core molecular function. Keep as non-core (duplicate of the IBA malate-aspartate shuttle call). Supporting Evidence: Reactome:R-HSA-9856872 which subsequently gets coimported with a proton and transaminated back
GO:0005743 mitochondrial inner membrane	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity (ISS) restatement of the core mitochondrial inner-membrane location. Accept. Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	KEEP AS NON CORE	Summary: High-throughput mitochondrial-proteome mass-spectrometry localization to the mitochondrion. Correct but less specific than the mitochondrial inner-membrane annotations. Keep as non-core (subsumed by GO:0005743). Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane
GO:0050796 regulation of insulin secretion	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity restatement of the insulin-secretion regulatory role (By similarity). Downstream/contextual physiological role; keep as non-core. Supporting Evidence: file:human/SLC25A22/SLC25A22-uniprot.txt Plays a role
GO:0005280 amino acid:proton symporter activity	IDA PMID:11897791 Identification of the mitochondrial glutamate transporter. B...	ACCEPT	Summary: Core molecular function capturing the coupled mechanism: GC-1 co-transports glutamate with a proton (electroneutral H+/glutamate symport). Directly demonstrated by reconstitution of the bacterially expressed protein into liposomes (PMID:11897791). This is the most mechanism-specific MF available (no dedicated glutamate:proton symporter term exists in GO). Accept. Supporting Evidence: PMID:11897791 Glutamate is co-transported with H(+) (or exchanged for OH(-)) PMID:11897791 reconstituted into phospholipid vesicles
GO:0005280 amino acid:proton symporter activity	TAS Reactome:R-HSA-8875623	ACCEPT	Summary: Reactome-asserted amino acid:proton symporter activity for the SLC25A18/SLC25A22 glutamate/H+ import reaction. Duplicate of the IDA call for the same core MF. Accept. Supporting Evidence: Reactome:R-HSA-8875623 Glutamate (Glu) can be co-transported with H+ via SLC25A18 and SLC25A22
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-8875623	ACCEPT	Summary: Reactome-asserted mitochondrial inner-membrane location for the glutamate/H+ import reaction. Consistent with the core location. Accept. Supporting Evidence: Reactome:R-HSA-8875623 located on the inner mitochondrial membrane
GO:0005313 L-glutamate transmembrane transporter activity	IDA PMID:11897791 Identification of the mitochondrial glutamate transporter. B...	ACCEPT	Summary: Core molecular function (substrate specificity), directly demonstrated by functional reconstitution of GC-1 and characterization as a glutamate/H+ symporter (PMID:11897791). Accept. Supporting Evidence: PMID:11897791 the two proteins are isoforms of the glutamate/H(+) symporter described in the past in whole mitochondria
GO:0005743 mitochondrial inner membrane	IDA PMID:11897791 Identification of the mitochondrial glutamate transporter. B...	ACCEPT	Summary: Direct experimental support for the core mitochondrial inner-membrane location; GC-1 is a mitochondrial inner-membrane carrier characterized in this paper. Accept. Supporting Evidence: PMID:11897791 The mitochondrial carriers are a family of transport proteins in the inner membranes of mitochondria
GO:0015813 L-glutamate transmembrane transport	IDA PMID:11897791 Identification of the mitochondrial glutamate transporter. B...	ACCEPT	Summary: Core biological process, directly demonstrated: reconstituted GC-1 transports L-glutamate across the membrane in symport with H+ (PMID:11897791). Accept. Supporting Evidence: PMID:11897791 Glutamate is co-transported with H(+) (or exchanged for OH(-))

Gene Description

Existing Annotations Review

Core Functions

Imports L-glutamate from the cytosol into the mitochondrial matrix across the mitochondrial inner membrane in electroneutral symport with a proton (H+/glutamate symport, or glutamate/OH- exchange), supplying matrix glutamate for catabolism, transamination, and ammonia handling.

Acts as the specific L-glutamate transmembrane transporter of the mitochondrial inner membrane; loss of this activity (e.g. the DEE3 variant Pro206Leu) causes developmental and epileptic encephalopathy 3.

References

📚 Additional Documentation

Notes

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