id: Q9UJS0
gene_symbol: SLC25A13
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SLC25A13 encodes citrin (aspartate/glutamate carrier 2, AGC2), the liver-type,
  calcium-binding member of the mitochondrial carrier (SLC25) family. It is an
  integral, multi-pass protein of the mitochondrial inner membrane that catalyzes
  the electrogenic exchange of L-aspartate for L-glutamate plus a proton: it
  exports L-aspartate from the mitochondrial matrix to the cytosol while importing
  cytosolic L-glutamate together with a proton. Because aspartate moves as the anion
  and glutamate is co-transported with a proton, the antiport is electrogenic and, in
  energized mitochondria, is driven in the direction of aspartate efflux. Citrin
  is a central component of the malate-aspartate NADH shuttle, transferring
  cytosolic reducing equivalents into the mitochondria and regenerating cytosolic
  NAD+, and it supplies the cytosolic aspartate consumed by argininosuccinate
  synthetase (ASS1) in the hepatic urea cycle and used in gluconeogenesis. Each
  protomer has a three-domain architecture: an N-terminal regulatory domain with
  EF-hand motifs (only EF-hand 2 binds calcium in the intermembrane space), a
  six-transmembrane SLC25 carrier domain that performs transport, and a C-terminal
  amphipathic helix; the full-length carrier assembles as a homodimer via the
  N-terminal domain while transporting substrate as a functional monomer. Citrin is
  expressed most abundantly in liver and other non-excitable tissues, in contrast
  to its paralog aralar (SLC25A12 / AGC1), the brain- and muscle-predominant
  isoform. Loss of citrin function causes citrin deficiency, which manifests across
  age as neonatal intrahepatic cholestasis (NICCD), failure to thrive and
  dyslipidemia (FTTDCD), and adult-onset citrullinemia type II (CTLN2) with
  hyperammonemic encephalopathy; the phenotype is broader than that of a pure urea
  cycle enzyme owing to citrin's additional role in the malate-aspartate shuttle
  and cellular redox balance.
alternative_products:
- name: '1'
  id: Q9UJS0-1
- name: '2'
  id: Q9UJS0-2
  sequence_note: VSP_043747
existing_annotations:
- term:
    id: GO:0005313
    label: L-glutamate transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assignment of L-glutamate transporter activity. Citrin
      imports L-glutamate together with a proton as one half of its aspartate/glutamate
      antiport, so this is a correct component of the core function.
    action: ACCEPT
    reason: >-
      Directly supported by experimental reconstitution showing electrogenic exchange
      of aspartate for glutamate and a proton. This activity is one arm of the
      aspartate/glutamate antiport; the more specific antiporter term (GO:0000515) is
      the primary/core molecular function, but this term is accurate.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "shown to catalyze the electrogenic exchange of aspartate for glutamate and a H"
- term:
    id: GO:0015183
    label: L-aspartate transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assignment of L-aspartate transporter activity. Citrin exports
      L-aspartate from the matrix as the other half of its antiport; a correct component
      of the core function.
    action: ACCEPT
    reason: >-
      Experimentally demonstrated. Aspartate efflux is one arm of the electrogenic
      aspartate/glutamate antiport (the core activity, GO:0000515). This transporter-activity
      term is accurate.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "shown to catalyze the electrogenic exchange of aspartate for glutamate and a H"
- term:
    id: GO:0043490
    label: malate-aspartate shuttle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) assignment placing citrin in the malate-aspartate NADH shuttle,
      which it participates in as the inner-membrane aspartate/glutamate exchange step.
    action: ACCEPT
    reason: >-
      Well supported: overexpression of citrin increases malate-aspartate shuttle activity
      in human cells, and the carrier is an integral component of the shuttle. Core biological
      process for citrin.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "Overexpression of the carriers in transfected human cells increased the activity of the malate/aspartate NADH shuttle"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) assignment to the mitochondrial inner membrane, where citrin is
      active as a multi-pass carrier. Correct and core subcellular location.
    action: ACCEPT
    reason: >-
      Consistent with all experimental localization data and the multi-pass topology of
      the SLC25 carrier domain. Core location.
    supported_by:
    - reference_id: PMID:39419476
      supporting_text: "located in the mitochondrial inner membrane"
- term:
    id: GO:0015810
    label: aspartate transmembrane transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) BP assignment for aspartate transmembrane transport, the process
      arm of citrin's aspartate efflux.
    action: ACCEPT
    reason: >-
      Experimentally supported process term corresponding to the aspartate half of the
      antiport. Accurate.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "shown to catalyze the electrogenic exchange of aspartate for glutamate and a H"
- term:
    id: GO:0015813
    label: L-glutamate transmembrane transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) BP assignment for L-glutamate transmembrane transport, the process
      arm of citrin's glutamate import.
    action: ACCEPT
    reason: >-
      Experimentally supported process term corresponding to the glutamate half of the
      antiport. Accurate.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "shown to catalyze the electrogenic exchange of aspartate for glutamate and a H"
- term:
    id: GO:0000514
    label: '3-sulfino-L-alanine: proton, glutamate antiporter activity'
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      ARBA electronic annotation for cysteinesulfinate (3-sulfino-L-alanine) / glutamate,
      proton antiport. Citrin exchanges cysteinesulfinate with glutamate and a proton
      experimentally; correct but a secondary (non-core) substrate.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally demonstrated as a secondary substrate exchange, but aspartate/glutamate
      antiport (GO:0000515) is the physiologically central function. Real but ancillary.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "AGC also transports cysteinesulfinate in exchange for either aspartate or glutamate"
- term:
    id: GO:0000515
    label: aspartate:glutamate, proton antiporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      ARBA electronic annotation for the aspartate:glutamate, proton antiporter activity,
      the primary catalytic function of citrin. Duplicated by an EXP and an IDA annotation.
    action: ACCEPT
    reason: >-
      The primary/core molecular function of citrin, directly demonstrated by reconstitution
      and independently confirmed. The electronic annotation is correct.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "shown to catalyze the electrogenic exchange of aspartate for glutamate and a H"
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation (InterPro EF-hand) for calcium ion binding. Citrin has a
      regulatory N-terminal EF-hand domain; the structure confirms calcium binding at EF-hand 2.
    action: ACCEPT
    reason: >-
      Supported by X-ray structure showing calcium bound at EF-hand 2. Calcium binding is a
      genuine molecular activity of the regulatory domain.
    supported_by:
    - reference_id: PMID:25410934
      supporting_text: "Only EF-hand 2 binds calcium"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation (multiple IEA methods / UniProt SubCell) for mitochondrial inner
      membrane localization. Correct and duplicated by EXP/IDA annotations.
    action: ACCEPT
    reason: >-
      Consistent with experimental subcellular localization. Core location.
    supported_by:
    - reference_id: PMID:39419476
      supporting_text: "located in the mitochondrial inner membrane"
- term:
    id: GO:0015804
    label: neutral amino acid transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      Inter-ontology (GO_REF:0000108) inference from the cysteinesulfinate antiport term
      GO:0000514, classifying cysteinesulfinate transport as neutral amino acid transport.
    action: MODIFY
    reason: >-
      Citrin's physiological substrates aspartate and glutamate are acidic (anionic) amino acids,
      not neutral amino acids. This term is a logical by-product of the secondary cysteinesulfinate
      activity and mischaracterizes the core function; better captured by the aspartate/glutamate
      transport terms.
    proposed_replacement_terms:
    - id: GO:0015810
      label: aspartate transmembrane transport
    - id: GO:0015813
      label: L-glutamate transmembrane transport
- term:
    id: GO:0043490
    label: malate-aspartate shuttle
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to the malate-aspartate shuttle, duplicating the IBA and IDA
      annotations to this term.
    action: ACCEPT
    reason: >-
      Correct; the malate-aspartate shuttle is a core biological process for citrin, independently
      supported by experimental data.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "Overexpression of the carriers in transfected human cells increased the activity of the malate/aspartate NADH shuttle"
- term:
    id: GO:0051592
    label: response to calcium ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation for response to calcium ion, reflecting calcium stimulation of
      citrin transport activity via its EF-hand domain.
    action: KEEP_AS_NON_CORE
    reason: >-
      Citrin transport is stimulated by calcium binding at the intermembrane-space EF-hand domain,
      so a response-to-calcium annotation has an experimental basis. However this is a
      regulatory/response process rather than citrin's core transport function. Retain as non-core.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "stimulated by Ca"
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation to the generic transmembrane transport process from the
      mitochondrial carrier domain signature.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but very general parent term. The specific aspartate/glutamate transport processes
      and the malate-aspartate shuttle capture the core function; this broad term is a valid,
      non-core ancestor.
- term:
    id: GO:0070778
    label: L-aspartate transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation (from the aspartate transporter/antiporter MF terms) for L-aspartate
      transmembrane transport, the process arm of citrin's aspartate efflux.
    action: ACCEPT
    reason: >-
      Accurate specific process term for aspartate transport, consistent with the experimentally
      demonstrated aspartate efflux activity.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "shown to catalyze the electrogenic exchange of aspartate for glutamate and a H"
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      Inter-ontology inference (from GO:0000514) that citrin is involved in proton transmembrane
      transport, reflecting co-transport of a proton with glutamate.
    action: KEEP_AS_NON_CORE
    reason: >-
      Citrin co-transports a proton with glutamate, so proton translocation is part of its
      electrogenic mechanism; not wrong, but a mechanistic by-product rather than the primary
      amino-acid antiport function. Retain as non-core.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "shown to catalyze the electrogenic exchange of aspartate for glutamate and a H"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      High-throughput interactome (IPI) annotation with the paralog SLC25A12 / aralar (O75746) as
      the recorded partner. Uninformative bare protein-binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, bare protein binding conveys no specific function. The recorded
      partner is the paralog SLC25A12, consistent with the mitochondrial-carrier context, but this
      generic term does not describe citrin's molecular function. The informative interaction
      (homodimerization) is captured by GO:0042802.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      High-throughput interactome (IPI) annotation with the paralog SLC25A12 (O75746). Uninformative
      bare protein-binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding is uninformative and is discouraged. Duplicate large-scale interactome hit
      against the paralog SLC25A12; does not add functional specificity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40355756
  qualifier: enables
  review:
    summary: >-
      Solute carrier interactome (IPI) annotation with the paralog SLC25A12 (O75746). Uninformative
      bare protein-binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding is uninformative. Large-scale SLC interactome hit against the paralog
      SLC25A12; no specific molecular function conveyed.
- term:
    id: GO:0005313
    label: L-glutamate transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Ensembl-Compara (GO_REF:0000107) orthology transfer from mouse Slc25a13 (Q9QXX4) of L-glutamate
      transporter activity. Duplicates the IBA annotation to this term.
    action: ACCEPT
    reason: >-
      Correct: glutamate import is one arm of citrin's antiport, well supported experimentally. The
      orthology transfer is appropriate.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "shown to catalyze the electrogenic exchange of aspartate for glutamate and a H"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Ensembl-Compara orthology transfer of mitochondrion localization. Correct but less specific
      than the mitochondrial inner membrane annotations.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate but a broad parent of the specific mitochondrial inner membrane location that is the
      core annotation. Retain as non-core.
    supported_by:
    - reference_id: PMID:39419476
      supporting_text: "located in the mitochondrial inner membrane"
- term:
    id: GO:0006094
    label: gluconeogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl-Compara orthology transfer for involvement in gluconeogenesis, reflecting the
      requirement for cytosolic aspartate (supplied by citrin) in gluconeogenesis from lactate.
    action: KEEP_AS_NON_CORE
    reason: >-
      Citrin-supplied cytosolic aspartate is needed for the conversion of oxoglutarate to
      oxaloacetate in gluconeogenesis from lactate/alanine, so the process link is physiologically
      valid but downstream and tissue-context dependent rather than a core molecular function.
      Retain as non-core.
    supported_by:
    - reference_id: PMID:25410934
      supporting_text: "Cytosolic aspartate is also required for the conversion of oxoglutarate to oxaloacetate, a crucial step in gluconeogenesis from lactate and alanine"
- term:
    id: GO:0015172
    label: acidic amino acid transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Ensembl-Compara orthology transfer of acidic amino acid transmembrane transporter activity, a
      parent term covering the transport of the acidic amino acids aspartate and glutamate.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct as a broader (parent) molecular function: aspartate and glutamate are acidic amino
      acids. The specific aspartate:glutamate antiporter activity (GO:0000515) and the individual
      aspartate/glutamate transporter terms are the core annotations; this generalization is a valid
      non-core ancestor.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence-based (HPA, IDA) mitochondrial localization. Consistent with the established
      mitochondrial inner-membrane location.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but less specific than mitochondrial inner membrane; retain as non-core. Human Protein
      Atlas reports SLC25A13 as tissue-enriched in liver with mitochondrial staining.
- term:
    id: GO:0000515
    label: aspartate:glutamate, proton antiporter activity
  evidence_type: EXP
  original_reference_id: PMID:38945283
  qualifier: enables
  review:
    summary: >-
      Experimental (EXP) confirmation of aspartate:glutamate, proton antiporter activity. Reconfirmed
      the canonical antiport and showed citrin does NOT transport GABA, sharpening substrate specificity.
    action: ACCEPT
    reason: >-
      Directly supports the primary/core molecular function; additionally excludes GABA as a substrate,
      refining specificity of the antiport.
    supported_by:
    - reference_id: PMID:38945283
      supporting_text: "the human AGC isoforms (AGC1/aralar1 and AGC2/citrin) are unable to transport GABA both in homo- and in hetero-exchange with either glutamate or aspartate, i.e. the canonical substrates of AGC"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: EXP
  original_reference_id: PMID:10642534
  qualifier: located_in
  review:
    summary: >-
      Experimental localization of citrin (Aralar2) to mitochondria in human cell lines. Core location,
      duplicated by other EXP/IDA/IBA annotations.
    action: ACCEPT
    reason: >-
      The mitochondrial localization of citrin was experimentally established in this characterization
      study; it is the core subcellular location.
    supported_by:
    - reference_id: PMID:10642534
      supporting_text: "The localization of Aralar2/citrin expressed in human cell lines is mitochondrial"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: EXP
  original_reference_id: PMID:39419476
  qualifier: located_in
  review:
    summary: >-
      Experimental localization to the mitochondrial inner membrane, from the domain-dissection study
      of citrin (which also showed N-terminal mutations cause a mitochondrial import defect). Core location.
    action: ACCEPT
    reason: >-
      Directly supported experimental annotation of the core inner-membrane location.
    supported_by:
    - reference_id: PMID:39419476
      supporting_text: "located in the mitochondrial inner membrane"
- term:
    id: GO:0043490
    label: malate-aspartate shuttle
  evidence_type: IGI
  original_reference_id: PMID:37647199
  qualifier: involved_in
  review:
    summary: >-
      Genetic-interaction (IGI) annotation from a panel of malate-aspartate-shuttle-deficient cell lines
      showing the shuttle (including its AGC component) is important for de novo serine biosynthesis.
      Places citrin in the malate-aspartate shuttle.
    action: ACCEPT
    reason: >-
      The malate-aspartate shuttle is a core biological process for citrin. This genetic study of MAS
      components (full text assessed by the curator) supports the shuttle involvement; the abstract
      confirms the MAS focus. Consistent with the IBA/IDA annotations to the same term.
    supported_by:
    - reference_id: PMID:37647199
      supporting_text: "we show that the MAS is important for de novo serine biosynthesis"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics (HTP) placement of SLC25A13 in the mitochondrion (high-confidence
      mitochondrial proteome). Consistent with the established mitochondrial inner-membrane location.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but broader than the specific mitochondrial inner-membrane location; a proteome-scale
      mitochondrial call. Retain as non-core.
- term:
    id: GO:0000514
    label: '3-sulfino-L-alanine: proton, glutamate antiporter activity'
  evidence_type: IDA
  original_reference_id: PMID:11566871
  qualifier: enables
  review:
    summary: >-
      Direct experimental (IDA) demonstration that citrin exchanges cysteinesulfinate
      (3-sulfino-L-alanine) for glutamate and a proton. A genuine but secondary substrate activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally demonstrated secondary substrate exchange. Physiologically the aspartate/glutamate
      antiport (GO:0000515) is central; cysteinesulfinate exchange is ancillary. Retain as accurate but
      non-core.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "AGC also transports cysteinesulfinate in exchange for either aspartate or glutamate"
- term:
    id: GO:0000515
    label: aspartate:glutamate, proton antiporter activity
  evidence_type: IDA
  original_reference_id: PMID:11566871
  qualifier: enables
  review:
    summary: >-
      Direct experimental (IDA) demonstration of the electrogenic aspartate:glutamate, proton antiport
      by reconstituted citrin. The defining, core molecular function.
    action: ACCEPT
    reason: >-
      The foundational experimental evidence for citrin's core function: reconstituted protein catalyzes
      electrogenic exchange of aspartate for glutamate and a proton. Primary molecular function.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "shown to catalyze the electrogenic exchange of aspartate for glutamate and a H"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:11566871
  qualifier: located_in
  review:
    summary: >-
      Direct experimental (IDA) inner-membrane localization with defined multi-pass topology (N- and
      C-terminal domains in the intermembrane space; six-TM carrier domain). Core location.
    action: ACCEPT
    reason: >-
      Directly supported experimental annotation of the core inner-membrane location and topology.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "Ca(2+)-stimulated aspartate/glutamate transporters"
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:25410934
  qualifier: enables
  review:
    summary: >-
      Direct experimental (IDA) calcium binding, from the X-ray structure of the citrin N-terminal domain
      showing calcium bound at EF-hand 2. Core molecular activity of the regulatory domain.
    action: ACCEPT
    reason: >-
      Crystallographic demonstration of calcium binding at EF-hand 2. Calcium binding by the regulatory
      EF-hand domain is a genuine, core molecular function of citrin.
    supported_by:
    - reference_id: PMID:25410934
      supporting_text: "Only EF-hand 2 binds calcium"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IDA
  original_reference_id: PMID:25410934
  qualifier: enables
  review:
    summary: >-
      Direct experimental (IDA) identical protein binding, reflecting the demonstrated homodimerization
      of citrin via its N-terminal domain (SEC-MALLS and the dimeric crystal structure).
    action: KEEP_AS_NON_CORE
    reason: >-
      Citrin forms a homodimer via the N-terminal domain, so identical protein binding is experimentally
      supported and more informative than bare protein binding. However dimerization is a structural
      property rather than the core transport function (the carrier transports substrate as a functional
      monomer). Retain as non-core.
    supported_by:
    - reference_id: PMID:25410934
      supporting_text: "demonstrating that the full-length carrier was dimeric"
- term:
    id: GO:0006839
    label: mitochondrial transport
  evidence_type: NAS
  original_reference_id: PMID:10642534
  qualifier: involved_in
  review:
    summary: >-
      Non-traceable author statement (NAS) that citrin functions in mitochondrial transport, from the
      initial characterization describing it as a calcium-regulated mitochondrial metabolite carrier.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but very general. The specific aspartate/glutamate antiport and its downstream processes
      (malate-aspartate shuttle, aspartate/glutamate transport) capture the core function; this broad
      process term is a valid non-core ancestor.
    supported_by:
    - reference_id: PMID:10642534
      supporting_text: "function as calcium-regulated metabolite (possibly anionic) carriers"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-372448
  qualifier: located_in
  review:
    summary: >-
      Traceable author statement (Reactome) for mitochondrial inner-membrane localization, from the
      Reactome reaction in which SLC25A12/13 exchange L-Glu and L-Asp. Core location.
    action: ACCEPT
    reason: >-
      Reactome curation consistent with all experimental localization data. Core inner-membrane location.
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:10642534
  qualifier: enables
  review:
    summary: >-
      Direct experimental (IDA) calcium binding from the initial characterization, where the N-terminal
      half of citrin was shown to bind calcium (requiring the two most distal EF-hands). Core molecular
      activity of the regulatory domain.
    action: ACCEPT
    reason: >-
      Experimentally demonstrated calcium binding by the N-terminal EF-hand domain. Duplicates the
      structurally-supported IDA calcium-binding annotation.
    supported_by:
    - reference_id: PMID:10642534
      supporting_text: "The N-terminal half of Aralar2/citrin is able to bind calcium and this requires the presence of the two most distal EF-hands"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:10642534
  qualifier: located_in
  review:
    summary: >-
      Direct experimental (IDA) mitochondrial localization of citrin expressed in human cell lines.
      Consistent with the inner-membrane location; broader term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate but a broad parent of the specific mitochondrial inner membrane location. Retain as
      non-core.
    supported_by:
    - reference_id: PMID:10642534
      supporting_text: "The localization of Aralar2/citrin expressed in human cell lines is mitochondrial"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity (ISS) transfer from mouse Slc25a13 (Q9QXX4) of inner-membrane localization.
      Correct and duplicated by EXP/IDA/IBA annotations.
    action: ACCEPT
    reason: >-
      Consistent with all experimental localization data. Core location.
    supported_by:
    - reference_id: PMID:39419476
      supporting_text: "located in the mitochondrial inner membrane"
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: NAS
  original_reference_id: PMID:10642534
  qualifier: located_in
  review:
    summary: >-
      Non-traceable author statement (NAS) placing citrin at the plasma membrane. Contradicts the
      extensive experimental evidence for a mitochondrial inner-membrane localization, including the
      conclusion of the same cited paper.
    action: REMOVE
    reason: >-
      Citrin is an integral protein of the mitochondrial inner membrane; there is no experimental
      support for a plasma-membrane location, and the cited characterization study itself concludes the
      localization is mitochondrial. This NAS annotation is inconsistent with established biology and
      should be removed.
    supported_by:
    - reference_id: PMID:10642534
      supporting_text: "The localization of Aralar2/citrin expressed in human cell lines is mitochondrial"
- term:
    id: GO:0006754
    label: ATP biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:12851387
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental (IDA) annotation that recombinant citrin increases mitochondrial ATP production
      in agonist-stimulated cells, linking its calcium-sensitive transport activity to mitochondrial
      energy metabolism.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported: citrin overexpression raises mitochondrial ATP upon calcium-mobilizing
      agonist stimulation, via its role in the malate-aspartate shuttle feeding reducing equivalents to
      oxidative phosphorylation. This is a downstream physiological consequence rather than citrin's
      direct molecular function; retain as non-core.
    supported_by:
    - reference_id: PMID:12851387
      supporting_text: "larger in cells expressing aralar and citrin"
- term:
    id: GO:0045333
    label: cellular respiration
  evidence_type: IDA
  original_reference_id: PMID:12851387
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental (IDA) annotation linking citrin to cellular respiration through its
      calcium-stimulated enhancement of mitochondrial ATP production and aerobic metabolism.
    action: KEEP_AS_NON_CORE
    reason: >-
      Citrin contributes to aerobic/oxidative metabolism by feeding cytosolic reducing equivalents into
      mitochondria via the malate-aspartate shuttle, and its overexpression stimulates mitochondrial ATP
      on agonist stimulation. Downstream physiological role rather than a core molecular function;
      retain as non-core.
    supported_by:
    - reference_id: PMID:12851387
      supporting_text: "the stimulation of aerobic metabolism"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:11566871
  qualifier: located_in
  review:
    summary: >-
      Direct experimental (IDA) mitochondrial localization from the functional reconstitution study.
      Consistent with the inner-membrane location; broader term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate but a broad parent of the specific mitochondrial inner membrane location. Retain as
      non-core.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "Ca(2+)-stimulated aspartate/glutamate transporters"
- term:
    id: GO:0015810
    label: aspartate transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:11566871
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental (IDA) aspartate transmembrane transport, the process arm of citrin's aspartate
      efflux, demonstrated by reconstitution.
    action: ACCEPT
    reason: >-
      Experimentally supported specific process term for aspartate transport (the aspartate half of the
      antiport). Accurate.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "shown to catalyze the electrogenic exchange of aspartate for glutamate and a H"
- term:
    id: GO:0015813
    label: L-glutamate transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:11566871
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental (IDA) L-glutamate transmembrane transport, the process arm of citrin's
      glutamate import, demonstrated by reconstitution.
    action: ACCEPT
    reason: >-
      Experimentally supported specific process term for glutamate transport (the glutamate half of the
      antiport). Accurate.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "shown to catalyze the electrogenic exchange of aspartate for glutamate and a H"
- term:
    id: GO:0043490
    label: malate-aspartate shuttle
  evidence_type: IDA
  original_reference_id: PMID:11566871
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental (IDA) annotation to the malate-aspartate shuttle: citrin overexpression
      increased malate-aspartate shuttle activity in human cells. Core biological process.
    action: ACCEPT
    reason: >-
      Foundational experimental evidence that citrin is a component of the malate-aspartate NADH shuttle.
      Core biological process.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "Overexpression of the carriers in transfected human cells increased the activity of the malate/aspartate NADH shuttle"
- term:
    id: GO:0051592
    label: response to calcium ion
  evidence_type: IDA
  original_reference_id: PMID:11566871
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental (IDA) annotation for response to calcium ion: citrin transport activity is
      stimulated by calcium on the external face of the inner membrane, where its EF-hand domains reside.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported calcium stimulation of transport, a genuine regulatory response. However
      it is a regulatory process rather than citrin's core transport function, and the physiological
      significance of the calcium regulation has since been debated. Retain as non-core.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "stimulated by Ca"
- term:
    id: GO:0000050
    label: urea cycle
  evidence_type: TAS
  original_reference_id: PMID:11566871
  qualifier: involved_in
  review:
    summary: >-
      Proposed new annotation. Citrin supplies the cytosolic aspartate consumed by argininosuccinate
      synthetase (ASS1) in the hepatic urea cycle; loss of this supply underlies the argininosuccinate
      synthetase deficiency and citrullinemia of citrin deficiency. Central role documented but not
      currently in the GOA for SLC25A13.
    action: NEW
    reason: >-
      The urea cycle role is a defining, textbook function of citrin and mechanistically explains
      citrullinemia type II, yet no urea cycle (GO:0000050) annotation exists in the current GOA. Adding
      it captures a core biological process. Supported by the primary functional paper and the structural
      review.
    supported_by:
    - reference_id: PMID:11566871
      supporting_text: "urea cycle and the aspartate/malate NADH shuttle"
    - reference_id: PMID:25410934
      supporting_text: "In liver, cytosolic aspartate is required for the urea cycle"
core_functions:
- description: >-
    Electrogenic mitochondrial-inner-membrane aspartate/glutamate antiporter: exports L-aspartate
    from the matrix to the cytosol in exchange for cytosolic L-glutamate plus a proton.
  molecular_function:
    id: GO:0000515
    label: aspartate:glutamate, proton antiporter activity
  directly_involved_in:
  - id: GO:0043490
    label: malate-aspartate shuttle
  - id: GO:0000050
    label: urea cycle
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:11566871
    supporting_text: "shown to catalyze the electrogenic exchange of aspartate for glutamate and a H"
- description: >-
    Calcium binding by the regulatory N-terminal EF-hand domain (EF-hand 2) in the mitochondrial
    intermembrane space, which modulates the carrier.
  molecular_function:
    id: GO:0005509
    label: calcium ion binding
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:25410934
    supporting_text: "Only EF-hand 2 binds calcium"
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10642534
  title: Characterization of a second member of the subfamily of calcium-binding mitochondrial
    carriers expressed in human non-excitable tissues.
  findings:
  - statement: >-
      Cloned citrin (Aralar2) as a liver / non-excitable-tissue calcium-binding mitochondrial
      carrier, 78.3% identical to Aralar1; localizes to mitochondria in human cell lines and
      binds calcium via its N-terminal EF-hands.
    supporting_text: "The localization of Aralar2/citrin expressed in human cell lines is mitochondrial"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache (full_text_available: false). Original characterization establishing
      citrin identity, mitochondrial localization and calcium binding; the plasma-membrane NAS
      annotation attributed to this paper contradicts its own mitochondrial conclusion.
- id: PMID:11566871
  title: Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters
    in mitochondria.
  findings:
  - statement: >-
      Reconstituted citrin catalyzes electrogenic exchange of aspartate for glutamate and a proton,
      identifying it as the mitochondrial aspartate/glutamate carrier; overexpression increases
      malate-aspartate shuttle activity, and the activity is calcium-stimulated.
    supporting_text: "shown to catalyze the electrogenic exchange of aspartate for glutamate and a H"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available and verified. Foundational functional paper for citrin's core molecular
      function, malate-aspartate shuttle role, calcium regulation, and urea cycle connection.
- id: PMID:12851387
  title: Recombinant expression of the Ca(2+)-sensitive aspartate/glutamate carrier
    increases mitochondrial ATP production in agonist-stimulated Chinese hamster ovary
    cells.
  findings:
  - statement: >-
      Recombinant citrin (and aralar1) increase mitochondrial ATP production upon calcium-mobilizing
      agonist stimulation, linking calcium-sensitive aspartate/glutamate transport to mitochondrial
      energy metabolism.
    supporting_text: "larger in cells expressing aralar and citrin"
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache. Supports the downstream ATP-biosynthesis / cellular-respiration (non-core)
      annotations via the calcium-sensitive shuttle role.
- id: PMID:25410934
  title: Calcium-induced conformational changes of the regulatory domain of human
    mitochondrial aspartate/glutamate carriers.
  findings:
  - statement: >-
      X-ray structures of the citrin/aralar N- and C-terminal domains show a homodimer with a unique
      eight-EF-hand arch; only EF-hand 2 binds calcium, and calcium binding opens a vestibule regulating
      substrate access.
    supporting_text: "Only EF-hand 2 binds calcium"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available. Structural basis for calcium ion binding (IDA) and homodimerization
      (identical protein binding, IDA).
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interactome dataset; supports only a bare protein-binding IPI annotation with the
      paralog SLC25A12 (O75746). Not functionally informative for citrin.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interactome dataset; supports only a bare protein-binding IPI annotation with the
      paralog SLC25A12 (O75746).
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale mitochondrial localization evidence (HTP). Supports mitochondrion localization at a
      broad level.
- id: PMID:37647199
  title: The malate-aspartate shuttle is important for de novo serine biosynthesis.
  findings:
  - statement: >-
      Genetic disruption of malate-aspartate shuttle components (including the aspartate/glutamate carrier)
      reduces de novo serine biosynthesis, reflecting the shuttle's role in recycling cytosolic NADH to NAD+.
    supporting_text: "we show that the MAS is important for de novo serine biosynthesis"
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache (full text not available). Supports the malate-aspartate shuttle involvement
      (IGI); assessed as consistent with the well-established shuttle role, deferring to curator judgment on
      full text.
- id: PMID:38945283
  title: The mitochondrial aspartate/glutamate carrier does not transport GABA.
  findings:
  - statement: >-
      Human citrin (AGC2) and aralar (AGC1) transport aspartate and glutamate but do not transport GABA in
      homo- or hetero-exchange, refining the substrate specificity of the aspartate/glutamate antiport.
    supporting_text: "the human AGC isoforms (AGC1/aralar1 and AGC2/citrin) are unable to transport GABA both in homo- and in hetero-exchange with either glutamate or aspartate, i.e. the canonical substrates of AGC"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache. EXP re-confirmation of the aspartate:glutamate antiport (GO:0000515) and
      exclusion of GABA as a substrate.
- id: PMID:39419476
  title: Distinct roles for the domains of the mitochondrial aspartate/glutamate carrier
    citrin in organellar localization and substrate transport.
  findings:
  - statement: >-
      Domain-dissection with 33 pathogenic variants: the carrier domain performs transport (identifying
      substrate-binding and dynamics residues), while N-terminal domain mutations cause a mitochondrial
      import defect rather than regulating transport via calcium.
    supporting_text: "located in the mitochondrial inner membrane"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available. Supports inner-membrane localization (EXP) and reassigns the role of the
      N-terminal domain to organellar import; relevant caveat for calcium-regulation annotations.
- id: PMID:40355756
  title: The solute carrier superfamily interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale SLC interactome dataset; supports only a bare protein-binding IPI annotation with the
      paralog SLC25A12 (O75746).
- id: Reactome:R-HSA-372448
  title: SLC25A12,13 exchange L-Glu and L-Asp
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome curation of the aspartate/glutamate exchange, consistent with the core function and
      inner-membrane location.