id: Q02221
gene_symbol: COX6A2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: COX6A2 (cytochrome c oxidase subunit 6A2, mitochondrial; also called cytochrome
  c oxidase polypeptide VIa-heart / VIA-muscle) is the heart- and skeletal-muscle-specific
  nuclear-encoded structural (supernumerary) subunit 6A of mitochondrial respiratory
  Complex IV (cytochrome c oxidase), the terminal enzyme of the electron transport
  chain. It is a small, single-pass protein of the mitochondrial inner membrane and
  is non-catalytic; the catalytic core of Complex IV is formed by the three mitochondrially
  encoded subunits MT-CO1, MT-CO2 and MT-CO3. COX6A2 sits at the monomer-monomer interface
  of the complex and contributes to Complex IV assembly, stabilization and dimerization,
  and to modulation of oxidative phosphorylation. COX6A1 is the ubiquitously expressed
  paralogous isoform, whereas COX6A2 expression is restricted to heart and skeletal
  muscle. Biallelic loss-of-function variants in COX6A2 cause an autosomal recessive,
  muscle-specific mitochondrial complex IV (cytochrome c oxidase) deficiency (MC4DN18),
  presenting with infantile hypotonia and muscle weakness and, in some patients, respiratory
  insufficiency and cardiomyopathy, with reduced Complex IV levels and activity in
  skeletal muscle.
existing_annotations:
- term:
    id: GO:0006123
    label: mitochondrial electron transport, cytochrome c to oxygen
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: COX6A2 is a structural subunit of cytochrome c oxidase (Complex IV), the
      terminal enzyme that transfers electrons from reduced cytochrome c to molecular
      oxygen. This IBA annotation to the core biological process for a Complex IV subunit
      is correct and represents a core function of the gene.
    action: ACCEPT
    reason: Consistent with the phylogenetic assignment across the cytochrome c oxidase
      subunit 6A family and with the UniProt FUNCTION statement placing COX6A2 as a
      component of the enzyme that transfers electrons from cytochrome c to oxygen
      during oxidative phosphorylation.
    supported_by:
    - reference_id: file:human/COX6A2/COX6A2-uniprot.txt
      supporting_text: Component of the cytochrome c oxidase, the last enzyme in the
    - reference_id: file:human/COX6A2/COX6A2-uniprot.txt
      supporting_text: reduction of oxygen to water.
- term:
    id: GO:0045277
    label: respiratory chain complex IV
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: COX6A2 is one of the nuclear-encoded supernumerary subunits of Complex
      IV (cytochrome c oxidase). This is the current, correct cellular-component term
      for Complex IV membership and represents a core aspect of the gene.
    action: ACCEPT
    reason: UniProt SUBUNIT describes COX6A2 as a component of the 14-subunit cytochrome
      c oxidase complex; membership in respiratory chain complex IV is well established.
      (The obsolete term GO:0005751 is superseded by GO:0045277.)
    supported_by:
    - reference_id: file:human/COX6A2/COX6A2-uniprot.txt
      supporting_text: multisubunit enzyme composed of 14 subunits.
    - reference_id: file:human/COX6A2/COX6A2-uniprot.txt
      supporting_text: 11 supernumerary subunits COX4I1 (or
- term:
    id: GO:0030234
    label: enzyme regulator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: This IBA molecular-function annotation frames COX6A2 as a regulator of
      the cytochrome c oxidase enzyme. COX6A2 is, however, a non-catalytic structural
      (supernumerary) subunit whose characterized role is in assembly and stabilization
      of the complex rather than as a classical enzyme regulator. A structural molecule
      activity term more accurately captures its molecular function.
    action: MODIFY
    reason: UniProt describes COX6A2 as playing a role in assembly and stabilization
      of Complex IV, consistent with a scaffolding/structural role rather than enzyme
      regulation. Structural molecule activity (GO:0005198) better reflects the molecular
      contribution of this non-catalytic supernumerary subunit; it may additionally
      contribute to the overall cytochrome-c oxidase activity of the assembled complex.
    proposed_replacement_terms:
    - id: GO:0005198
      label: structural molecule activity
    supported_by:
    - reference_id: file:human/COX6A2/COX6A2-uniprot.txt
      supporting_text: Plays a role in the assembly and
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - ROLE_CONFLATION
      source_entities:
      - source_id: PANTHER:PTN000161400
        source_label: Cytochrome c oxidase subunit 6A family (PANTHER)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: The family-level 'enzyme regulator activity' call reflects reports
          that COX6A subunits modulate holoenzyme activity, but for the human subunit
          the well-supported molecular role is structural/assembly rather than enzyme
          regulation.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: COX6A2 is a single-pass mitochondrial inner-membrane protein, as expected
      for a Complex IV subunit. This is the correct and specific anatomical location
      of the gene product.
    action: ACCEPT
    reason: UniProt SUBCELLULAR LOCATION and the transmembrane topology features support
      inner-membrane localization; multiple independent lines of evidence (IEA, ISS,
      Reactome TAS) agree.
    supported_by:
    - reference_id: file:human/COX6A2/COX6A2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0045277
    label: respiratory chain complex IV
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: Electronically transferred (Ensembl Compara) annotation placing COX6A2
      in respiratory chain complex IV. This duplicates and is consistent with the
      IBA Complex IV membership annotation and is correct.
    action: ACCEPT
    reason: Complex IV membership is well supported by UniProt SUBUNIT; this is the
      current, correct cellular-component term.
    supported_by:
    - reference_id: file:human/COX6A2/COX6A2-uniprot.txt
      supporting_text: multisubunit enzyme composed of 14 subunits.
- term:
    id: GO:0006119
    label: oxidative phosphorylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: As a subunit of the terminal oxidase of the electron transport chain,
      COX6A2 participates in oxidative phosphorylation. This is a correct, if broad,
      biological-process annotation.
    action: ACCEPT
    reason: UniProt PATHWAY assigns COX6A2 to energy metabolism / oxidative phosphorylation;
      the more specific process (GO:0006123) is also annotated.
    supported_by:
    - reference_id: file:human/COX6A2/COX6A2-uniprot.txt
      supporting_text: 'PATHWAY: Energy metabolism; oxidative phosphorylation.'
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity-based inner-membrane localization, transferred from
      the bovine ortholog (P07471). Correct and consistent with the direct topology
      evidence.
    action: ACCEPT
    reason: Inner-membrane localization is established for the cytochrome c oxidase
      subunit 6A family and supported by UniProt SUBCELLULAR LOCATION.
    supported_by:
    - reference_id: file:human/COX6A2/COX6A2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput mitochondrial proteomics detected COX6A2 as a mitochondrial
      protein. This is correct, though less specific than the inner-membrane localization
      also annotated.
    action: ACCEPT
    reason: Supported by a quantitative high-confidence human mitochondrial proteome
      study; consistent with COX6A2 being a mitochondrial inner-membrane Complex IV
      subunit. Broad but not incorrect.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: Quantitative high-confidence human mitochondrial proteome and
        its dynamics in cellular context.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-163214
  qualifier: located_in
  review:
    summary: Reactome (electron transfer from reduced cytochrome c to molecular oxygen)
      places COX6A2 in the mitochondrial inner membrane as part of Complex IV. Correct.
    action: ACCEPT
    reason: Consistent with the established inner-membrane localization of Complex
      IV subunits; a curated Reactome traceable assertion.
    supported_by:
    - reference_id: Reactome:R-HSA-163214
      supporting_text: Complex IV (COX, cytochrome c oxidase) contains the hemeprotein
        cytochrome a and a3.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9709406
  qualifier: located_in
  review:
    summary: Reactome (CO binds to cytochrome c oxidase) localizes COX6A2 to the mitochondrial
      inner membrane as a Complex IV subunit. Correct location.
    action: ACCEPT
    reason: Consistent with inner-membrane localization of Complex IV; curated Reactome
      traceable assertion.
    supported_by:
    - reference_id: Reactome:R-HSA-9709406
      supporting_text: CO binds to cytochrome c oxidase, the terminal enzyme in the
        electron transfer chain
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9865663
  qualifier: located_in
  review:
    summary: Reactome models the final Complex IV assembly step in which COX6A (with
      other subunits) binds the holo-MT-CO1,2 complex in the inner membrane. This
      both localizes COX6A2 to the inner membrane and supports its role in Complex
      IV assembly.
    action: ACCEPT
    reason: Curated Reactome traceable assertion placing COX6A among the final assembly
      subunits of Complex IV in the inner membrane; consistent with the structural/assembly
      role of COX6A2.
    supported_by:
    - reference_id: Reactome:R-HSA-9865663
      supporting_text: The final assembly of Complex IV consists of binding of the
        MT-CO3, COX6A, COX6B, COX7A, and NDUFA4 subunits to the holo-MT-CO1, MT-CO2
        complex
- term:
    id: GO:0006091
    label: generation of precursor metabolites and energy
  evidence_type: TAS
  original_reference_id: PMID:9284905
  qualifier: involved_in
  review:
    summary: This broad energy-metabolism biological-process term is essentially correct
      for a Complex IV subunit (Complex IV drives energy generation), but it is a
      high-level parent of the more specific and more informative GO:0006123 that
      is already annotated. In addition, the cited reference PMID:9284905 is a mapping/pseudogene-assignment
      paper about the paralog COX6A1 (and the COX6A1P pseudogene), not COX6A2, and
      does not specifically support this gene's function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is a very general ancestor of the specific process already captured
      by GO:0006123 (mitochondrial electron transport, cytochrome c to oxygen), and
      the supporting ProtInc reference concerns the COX6A1 paralog rather than COX6A2,
      so it adds no specific, well-supported information for this gene.
    supported_by:
    - reference_id: PMID:9284905
      supporting_text: Assignment of COX6A1 to 6p21 and a pseudogene (COX6A1P) to 1p31.1
        by in situ hybridization and somatic cell hybrids.
core_functions:
- description: Non-catalytic structural subunit of mitochondrial respiratory Complex
    IV (cytochrome c oxidase) that contributes to complex assembly and stability and
    to the transfer of electrons from cytochrome c to molecular oxygen in the mitochondrial
    inner membrane.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  supported_by:
  - reference_id: file:human/COX6A2/COX6A2-uniprot.txt
    supporting_text: Plays a role in the assembly and
  contributes_to_molecular_function:
    id: GO:0004129
    label: cytochrome-c oxidase activity
  directly_involved_in:
  - id: GO:0006123
    label: mitochondrial electron transport, cytochrome c to oxygen
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0045277
    label: respiratory chain complex IV
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:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  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:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: High-throughput mitochondrial proteome; supports mitochondrial localization
      (GO:0005739) of COX6A2.
- id: PMID:9284905
  title: Assignment of COX6A1 to 6p21 and a pseudogene (COX6A1P) to 1p31.1 by in situ
    hybridization and somatic cell hybrids.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: Cited (ProtInc/PINC, TAS) for GO:0006091 on COX6A2, but the paper
      is a chromosomal-mapping study of the paralog COX6A1 and the COX6A1P pseudogene,
      not COX6A2. Wrong-gene citation for a broad energy-metabolism term.
- id: file:human/COX6A2/COX6A2-uniprot.txt
  title: UniProtKB entry Q02221 (CX6A2_HUMAN)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary UniProt record for COX6A2; source for function, complex membership,
      inner-membrane localization, tissue specificity and disease (MC4DN18).
- id: Reactome:R-HSA-163214
  title: Electron transfer from reduced cytochrome c to molecular oxygen
  findings: []
- id: Reactome:R-HSA-9709406
  title: CO binds to Cytochrome c oxidase
  findings: []
- id: Reactome:R-HSA-9865663
  title: MT-CO3, COX6A,B,7A and NDUFA4 bind to holo-MT-CO1,2 complex
  findings: []