id: O43772
gene_symbol: SLC25A20
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SLC25A20 is the mitochondrial carnitine/acylcarnitine carrier (also called
  carnitine-acylcarnitine translocase, CACT/CAC), an integral multi-pass protein
  of the mitochondrial inner membrane belonging to the mitochondrial carrier
  (SLC25) family. It catalyzes the electroneutral exchange (antiport) of
  long-chain O-acyl-L-carnitines for free L-carnitine across the inner membrane,
  and at lower rates the uniport of free carnitine. This activity is the central
  step of the mitochondrial carnitine shuttle: carnitine palmitoyltransferase 1
  (CPT1) on the outer membrane converts acyl-CoA to acylcarnitine, SLC25A20
  imports the acylcarnitine into the matrix while exporting free carnitine, and
  carnitine palmitoyltransferase 2 (CPT2) on the matrix face of the inner
  membrane regenerates acyl-CoA for fatty acid beta-oxidation. SLC25A20 is thus
  essential for delivering long-chain fatty acids into the matrix for energy
  production, especially during fasting and metabolic stress. Loss-of-function
  variants cause carnitine-acylcarnitine translocase deficiency, a severe
  autosomal-recessive long-chain fatty acid oxidation disorder presenting mostly
  in the neonatal period with hypoketotic hypoglycemia, hyperammonemia,
  cardiomyopathy, cardiac arrhythmia, and high mortality.
existing_annotations:
- term:
    id: GO:0005740
    label: mitochondrial envelope
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      SLC25A20 is an integral protein of the mitochondrial inner membrane; the
      mitochondrial envelope is a correct but less precise cellular component.
    action: ACCEPT
    reason: >-
      SLC25A20 is a multi-pass mitochondrial inner-membrane carrier, and the
      inner membrane is part of the mitochondrial envelope. This phylogenetic
      (IBA) call is consistent with the more specific inner-membrane annotations
      and with the UniProt subcellular location; retained as a correct broader
      component. The more informative location is captured by GO:0005743.
    supported_by:
    - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion inner membrane; Multi-pass membrane"
- term:
    id: GO:0006839
    label: mitochondrial transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      SLC25A20 mediates transport across the mitochondrial inner membrane
      (acylcarnitine/carnitine exchange); mitochondrial transport is a correct
      broad parent process.
    action: ACCEPT
    reason: >-
      As a mitochondrial carrier that moves acylcarnitines and carnitine across
      the inner membrane, SLC25A20 participates in mitochondrial transport. This
      is an accurate but general term; the specific carnitine/acylcarnitine
      transport processes are captured by GO:1902603 and GO:1902616 and the
      carnitine shuttle by GO:0006853.
    supported_by:
    - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
      supporting_text: >-
        Mediates the electroneutral exchange of acylcarnitines (O-
        acyl-(R)-carnitine or L-acylcarnitine) of different acyl chain lengths
- term:
    id: GO:0015227
    label: O-acyl-L-carnitine transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      SLC25A20 transports O-acyl-L-carnitines across the inner mitochondrial
      membrane; this is a correct molecular function, the transporter-parent of
      the more precise antiporter term.
    action: ACCEPT
    reason: >-
      The phylogenetic call correctly assigns acylcarnitine transporter activity,
      supported by direct functional characterization of the human carrier. It is
      a valid parent of GO:0005476 (carnitine:O-acyl-L-carnitine antiporter
      activity), which is the mechanistically precise molecular function.
    supported_by:
    - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
      supporting_text: >-
        it translocates the fatty acids in the form of
        acylcarnitines into the mitochondrial matrix
- term:
    id: GO:1902603
    label: carnitine transmembrane transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      SLC25A20 transports free carnitine across the inner membrane (as the
      counter-substrate of the antiport and by lower-rate uniport).
    action: ACCEPT
    reason: >-
      Carnitine transmembrane transport is directly supported: SLC25A20 exchanges
      acylcarnitine for free (R)-carnitine and also catalyzes unidirectional
      carnitine uniport. Correct process annotation.
    supported_by:
    - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
      supporting_text: >-
        Catalyzes the unidirectional transport
        (uniport) of carnitine at lower rates than the antiport (exchange)
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      SLC25A20 is a multi-pass integral protein of the mitochondrial inner
      membrane; this is its precise, correct location.
    action: ACCEPT
    reason: >-
      The electronic subcellular-location inference matches the UniProt
      curated location and the biology of the carnitine shuttle (inner-membrane
      carrier). Core cellular component.
    supported_by:
    - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion inner membrane; Multi-pass membrane"
- term:
    id: GO:1902616
    label: O-acyl-L-carnitine transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      SLC25A20 mediates transmembrane transport of O-acyl-L-carnitines into the
      matrix; correct process.
    action: ACCEPT
    reason: >-
      This IEA process term is the biological-process counterpart of the
      acylcarnitine transporter/antiporter molecular function and is directly
      supported by the carrier's characterized activity. Accept.
    supported_by:
    - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
      supporting_text: >-
        it translocates the fatty acids in the form of
        acylcarnitines into the mitochondrial matrix
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" from a large-scale yeast two-hybrid interactome
      screen (IntAct records an interaction with LAMP2, P13473-2). Uninformative
      as a molecular function for this carrier.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, generic "protein binding" does not convey the
      protein's actual function and is not a core molecular function of a
      solute carrier. The interaction comes from a high-throughput
      neurodegenerative-disease Y2H interactome (IntAct with/from
      UniProtKB:P13473-2, LAMP2), with no evidence it reflects a functional
      partnership relevant to carnitine transport. Retained (experimental IPI,
      not removed) but flagged as over-annotated / non-core.
    supported_by:
    - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
      supporting_text: "O43772; P13473-2: LAMP2; NbExp=3; IntAct=EBI-727085, EBI-21591415;"
- term:
    id: GO:0006853
    label: carnitine shuttle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      SLC25A20 is the inner-membrane translocase step of the mitochondrial
      carnitine shuttle; core biological process.
    action: ACCEPT
    reason: >-
      The carnitine shuttle couples CPT1 (outer membrane), CACT/SLC25A20 (inner
      membrane exchange), and CPT2 (matrix) to deliver long-chain fatty acids for
      beta-oxidation. This orthology-based IEA is correct and central to the
      gene's function.
    supported_by:
    - reference_id: Reactome:R-HSA-200425
      supporting_text: >-
        This transport system consists of the malonyl-CoA sensitive carnitine
        palmitoyltransferase I (CPT-I) localized in the mitochondrial outer
        membrane, the carnitine:acylcarnitine translocase, an integral inner
        membrane protein, and carnitine palmitoyltransferase II
- term:
    id: GO:0006853
    label: carnitine shuttle
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-200425
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable assertion that SLC25A20 acts in the carnitine shuttle;
      duplicate of the IEA call and equally correct.
    action: ACCEPT
    reason: >-
      Reactome curates SLC25A20 as the inner-membrane translocase of the
      carnitine shuttle. Consistent with the UniProt function and the disease
      mechanism; core process.
    supported_by:
    - reference_id: Reactome:R-HSA-200425
      supporting_text: >-
        The mitochondrial carnitine system catalyzes the transport of long-chain
        fatty acids  into the mitochondrial matrix where they undergo beta oxidation.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence (HPA) localizes SLC25A20 to the mitochondrion; correct
      but less precise than the inner-membrane annotation.
    action: ACCEPT
    reason: >-
      Direct immunofluorescence localization to mitochondria is consistent with
      the curated inner-membrane location. Accept as a correct, if general,
      cellular component (GO:0005743 is the more informative term).
    supported_by:
    - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
      supporting_text: "GO:0005739; C:mitochondrion; IDA:HPA."
- term:
    id: GO:0005476
    label: carnitine:O-acyl-L-carnitine antiporter activity
  evidence_type: EXP
  original_reference_id: PMID:9399886
  qualifier: enables
  review:
    summary: >-
      Experimentally supported core molecular function: SLC25A20 catalyzes the
      antiport (exchange) of O-acyl-L-carnitine for free carnitine across the
      inner mitochondrial membrane.
    action: ACCEPT
    reason: >-
      This is the defining molecular function of the gene product. The cloned
      human carnitine-acylcarnitine carrier was shown to translocate long-chain
      fatty acids (as acylcarnitines) across the inner mitochondrial membrane,
      and reconstituted-carrier work (UniProt-cited PubMed:12892634, 18307102,
      20347717) establishes the electroneutral antiport mechanism. Core MF.
    supported_by:
    - reference_id: PMID:9399886
      supporting_text: >-
        The carnitine-acylcarnitine carrier (CAC) catalyzes the translocation of
        long-chain fatty acids across the inner mitochondrial membrane.
    - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
      supporting_text: >-
        Mediates the electroneutral exchange of acylcarnitines (O-
        acyl-(R)-carnitine or L-acylcarnitine) of different acyl chain lengths
- term:
    id: GO:0005476
    label: carnitine:O-acyl-L-carnitine antiporter activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9971094
  qualifier: enables
  review:
    summary: >-
      Reactome traceable assertion of the carnitine:acylcarnitine antiporter
      activity; duplicate of the EXP call and equally correct.
    action: ACCEPT
    reason: >-
      Reactome curates SLC25A20 as the carrier that exchanges acylcarnitine for
      carnitine across the inner membrane (and can reverse to export excess
      acylcarnitine down the substrate gradient). Same core molecular function.
    supported_by:
    - reference_id: Reactome:R-HSA-9971094
      supporting_text: >-
        Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20, CACT) exports
        excess acylcarnitines out of mitochondria.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      SLC25A20 was identified in the high-confidence human mitochondrial proteome
      (MitoCoP) by quantitative mass spectrometry; consistent with mitochondrial
      localization.
    action: ACCEPT
    reason: >-
      High-throughput proteomic identification in a curated high-confidence
      mitochondrial proteome corroborates mitochondrial localization. Correct but
      less precise than the inner-membrane annotation; retained.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: >-
        defined a
        mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)
- term:
    id: GO:0015227
    label: O-acyl-L-carnitine transmembrane transporter activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity transfer (from rodent ortholog UniProtKB:P97521) of
      acylcarnitine transporter activity; correct.
    action: ACCEPT
    reason: >-
      The ISS transfer of O-acyl-L-carnitine transporter activity from the
      well-characterized ortholog is consistent with the experimentally
      established human activity. Valid parent of the antiporter MF; accept.
    supported_by:
    - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
      supporting_text: >-
        it translocates the fatty acids in the form of
        acylcarnitines into the mitochondrial matrix
- term:
    id: GO:1902603
    label: carnitine transmembrane transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer of carnitine transmembrane transport; correct
      (carnitine is the counter-substrate and a uniport substrate).
    action: ACCEPT
    reason: >-
      Consistent with the experimentally documented carnitine antiport/uniport by
      the human carrier. Duplicate of the IBA carnitine-transport call; accept.
    supported_by:
    - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
      supporting_text: >-
        Catalyzes the unidirectional transport
        (uniport) of carnitine at lower rates than the antiport (exchange)
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:20833797
  qualifier: located_in
  review:
    summary: >-
      SLC25A20 was detected among inner-membrane solute carriers in the
      phosphoproteome of isolated human muscle mitochondria; supports
      mitochondrial localization.
    action: ACCEPT
    reason: >-
      High-throughput proteomic detection in purified human muscle mitochondria
      (which included inner-membrane solute carriers) corroborates mitochondrial
      localization. Correct but less precise than the inner-membrane term.
    supported_by:
    - reference_id: PMID:20833797
      supporting_text: >-
        outer or inner membrane solute carriers and channel proteins
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-200424
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assertion that the SLC25A20 carrier is embedded in the
      inner mitochondrial membrane; core location.
    action: ACCEPT
    reason: >-
      Reactome curates the carnitine-acylcarnitine transporter as an
      inner-membrane protein mediating the acylcarnitine/carnitine exchange.
      Consistent with UniProt; core cellular component.
    supported_by:
    - reference_id: Reactome:R-HSA-200424
      supporting_text: >-
        The carnitine-acylcarnitine transporter (SLC25A20 / CACT), embedded in the
        inner mitochondrial membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9971094
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assertion of inner-membrane localization; duplicate of
      the R-HSA-200424 call and equally correct.
    action: ACCEPT
    reason: >-
      SLC25A20 exports/exchanges acylcarnitine across the inner membrane as an
      integral IMM carrier; core cellular component.
    supported_by:
    - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion inner membrane; Multi-pass membrane"
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: IC
  original_reference_id: PMID:9399886
  qualifier: involved_in
  review:
    summary: >-
      SLC25A20 is required for mitochondrial long-chain fatty acid beta-oxidation:
      by importing acylcarnitines into the matrix it delivers the substrate that
      CPT2 converts back to acyl-CoA for the beta-oxidation spiral.
    action: NEW
    reason: >-
      The carnitine shuttle exists to enable fatty acid beta-oxidation, and
      UniProt explicitly states SLC25A20 translocates fatty acids (as
      acylcarnitines) into the matrix "to undergo fatty acid beta-oxidation".
      Loss of SLC25A20 blocks long-chain FAO, causing CACT deficiency. This
      process is not captured elsewhere in the GOA set (which has the carnitine
      shuttle and transport processes but not the beta-oxidation process), so it
      is proposed as a NEW involved_in annotation. Inferred from the
      curator-established role (IC) with the cloning paper as anchor reference.
    supported_by:
    - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
      supporting_text: >-
        it translocates the fatty acids in the form of
        acylcarnitines into the mitochondrial matrix, where the carnitine
        palmitoyltransferase 2 (CPT-2) activates them to undergo fatty acid
        beta-oxidation
core_functions:
- description: >-
    Carnitine:O-acyl-L-carnitine antiporter of the mitochondrial inner membrane:
    catalyzes the electroneutral exchange of long-chain O-acyl-L-carnitine for
    free L-carnitine (and at lower rates carnitine uniport), the translocase step
    of the carnitine shuttle that delivers long-chain fatty acids into the matrix
    for beta-oxidation.
  molecular_function:
    id: GO:0005476
    label: carnitine:O-acyl-L-carnitine antiporter activity
  directly_involved_in:
  - id: GO:0006853
    label: carnitine shuttle
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:9399886
    supporting_text: >-
      The carnitine-acylcarnitine carrier (CAC) catalyzes the translocation of
      long-chain fatty acids across the inner mitochondrial membrane.
  - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
    supporting_text: >-
      Mediates the electroneutral exchange of acylcarnitines (O-
      acyl-(R)-carnitine or L-acylcarnitine) of different acyl chain lengths
- description: >-
    Delivery of long-chain fatty acids (as acylcarnitines) into the mitochondrial
    matrix for fatty acid beta-oxidation; SLC25A20 transports acylcarnitine across
    the inner membrane so CPT2 can regenerate acyl-CoA for the beta-oxidation
    spiral.
  molecular_function:
    id: GO:0015227
    label: O-acyl-L-carnitine transmembrane transporter activity
  directly_involved_in:
  - id: GO:0006635
    label: fatty acid beta-oxidation
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: file:human/SLC25A20/SLC25A20-uniprot.txt
    supporting_text: >-
      Key player in the mitochondrial
      oxidation pathway, it translocates the fatty acids in the form of
      acylcarnitines into the mitochondrial matrix, where the carnitine
      palmitoyltransferase 2 (CPT-2) activates them to undergo fatty acid
      beta-oxidation
  - reference_id: Reactome:R-HSA-200425
    supporting_text: >-
      The mitochondrial carnitine system catalyzes the transport of long-chain
      fatty acids  into the mitochondrial matrix where they undergo beta oxidation.
references:
- 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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:20833797
  title: Phosphoproteome analysis of functional mitochondria isolated from resting
    human muscle reveals extensive phosphorylation of inner membrane protein complexes
    and enzymes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale phosphoproteomics of purified human muscle mitochondria; supports
      mitochondrial localization of inner-membrane solute carriers but does not
      characterize SLC25A20 function specifically.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput Y2H neurodegenerative-disease interactome; source of the
      bare "protein binding" IPI (IntAct SLC25A20-LAMP2). Not informative about
      carnitine-transport function; supports only a generic interaction.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      MitoCoP high-confidence human mitochondrial proteome; corroborates
      mitochondrial localization but is not gene-specific functional evidence.
- id: PMID:9399886
  title: Cloning of the human carnitine-acylcarnitine carrier cDNA and identification
    of the molecular defect in a patient.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Foundational paper cloning the human CAC/CACT cDNA and identifying the first
      disease-causing mutation; establishes the inner-membrane translocation of
      long-chain fatty acids (as acylcarnitines). Basis for the EXP MF annotation.
- id: Reactome:R-HSA-200424
  title: Exchange of acylcarnitine and carnitine across the inner mitochondrial membrane
  findings: []
- id: Reactome:R-HSA-200425
  title: Carnitine shuttle
  findings: []
- id: Reactome:R-HSA-9971094
  title: SLC25A20 exports excess acyl-CAR
  findings: []
suggested_questions:
- question: >-
    What is the physiological acyl-chain-length preference of human SLC25A20 in
    situ, and does it transport medium-chain acylcarnitines efficiently enough to
    explain the acylcarnitine profile seen in CACT deficiency?
- question: >-
    Does SLC25A20 have any physiologically relevant protein partners at the inner
    membrane (e.g., functional coupling to CPT2 or the beta-oxidation machinery),
    beyond the high-throughput LAMP2 interaction?
suggested_experiments:
- description: >-
    Reconstitute recombinant human SLC25A20 into proteoliposomes and measure
    antiport kinetics (Km, Vmax) for a panel of acyl-carnitines of varying chain
    length versus free carnitine to define substrate specificity quantitatively.
- description: >-
    Use proximity labeling (BioID/APEX) of SLC25A20 in intact mitochondria to test
    for functional coupling with CPT2 and other inner-membrane fatty-acid
    oxidation components.