id: Q96I36
gene_symbol: COX14
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  COX14 (formerly C12orf62) is a small (57 aa, ~6.6 kDa) single-pass
  transmembrane protein of the mitochondrial inner membrane that acts as an
  early assembly factor for respiratory chain Complex IV (cytochrome c oxidase,
  COX). It is a core component of the MITRAC complex (mitochondrial translation
  regulation assembly intermediate of cytochrome c oxidase), where, together
  with COA3 and other MITRAC/assembly components, it associates with the
  newly-synthesised mtDNA-encoded core subunit MT-CO1 (COX1) and couples MT-CO1
  synthesis with its incorporation into the nascent enzyme, thereby regulating
  the early steps of COX assembly. COX14 is non-catalytic and has no known
  enzymatic activity; it functions as a scaffolding/regulatory assembly factor.
  Loss of COX14 destabilises newly synthesised COX1 and impairs COX assembly.
  In humans, biallelic COX14 variants cause mitochondrial complex IV deficiency,
  nuclear type 10 (MC4DN10), a fatal neonatal, Leigh-syndrome-like disorder with
  severe lactic acidosis.
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation placing COX14 in the mitochondrion. Correct
      but non-specific; the protein is more precisely localised to the
      mitochondrial inner membrane, where COX assembly occurs.
    action: ACCEPT
    reason: >-
      COX14 is unambiguously a mitochondrial protein (its yeast ortholog COX14
      and human C12orf62 both localise to mitochondria and function in COX
      assembly). This general location is correct; the inner-membrane
      sub-localisation is captured by other annotations and by core_functions.
    supported_by:
    - reference_id: PMID:22356826
      supporting_text: "Four of the proteins (AURKAIP1-, C7orf44-, C12orf62- and PET117-GFP) co-localize with the mitochondrial marker"
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation for the core biological process of COX14:
      assembly of mitochondrial respiratory chain complex IV. This is the
      well-supported, conserved function of COX14/Cox14 orthologs.
    action: ACCEPT
    reason: >-
      Directly matches the experimentally established role of COX14 as an early
      COX (Complex IV) assembly factor and MITRAC component. This is the core
      function of the gene and is supported by multiple experimental studies in
      addition to the phylogenetic inference.
    supported_by:
    - reference_id: PMID:22243966
      supporting_text: "C12orf62 is required for coordination of the early steps of COX assembly with"
    - reference_id: PMID:22356826
      supporting_text: "We experimentally confirm the role of C12orf62 as a COX assembly factor binding to COX1 and acting as its translation regulator"
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation to mitochondrial outer membrane, derived from the
      UniProt Subcellular Location keyword (SL-0172). This conflicts with the
      protein's function as a MITRAC/Complex IV assembly factor acting on
      MT-CO1, which occurs in the inner membrane, and with Reactome's placement
      of COX14 in the mitochondrial inner membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      COX14 engages the mtDNA-encoded core subunit MT-CO1 within the MITRAC
      assembly intermediate, a process that takes place in the mitochondrial
      inner membrane (where COX resides). Reactome consistently annotates COX14
      to the inner membrane (GO:0005743). The single-pass topology (N-terminus
      intermembrane, C-terminus in the matrix) is consistent with an
      inner-membrane protein. The outer-membrane assignment propagated from the
      SubCell keyword is therefore likely an over-annotation rather than the
      site of function; it is retained as non-core rather than removed because
      it derives from a curated UniProt subcellular-location statement.
    supported_by:
    - reference_id: file:human/COX14/COX14-uniprot.txt
      supporting_text: "TOPO_DOM        1..14"
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation to protein folding, logically inferred from the
      protein folding chaperone MF annotation (GO:0044183). COX14 is a
      scaffolding assembly factor, not a demonstrated protein-folding chaperone.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This IEA is derived by inter-ontology inference from the GO:0044183
      protein folding chaperone annotation, which itself over-interprets COX14's
      role. COX14 stabilises newly synthesised COX1 within an early assembly
      intermediate but has not been shown to catalyse polypeptide folding. The
      process is better described as Complex IV assembly (GO:0033617) than
      generic protein folding, so this annotation is marked as over-annotated.
    supported_by:
    - reference_id: PMID:28082314
      supporting_text: "CMC1 stabilizes a COX1-COA3-COX14 complex before the incorporation of COX4 and"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a high-throughput binary interactome screen
      (HuRI), recording a COX14 interaction with MESD (Q14696). This is an
      uninformative molecular-function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, bare 'protein binding' does not convey COX14's
      actual molecular function and is uninformative. The interaction (with
      MESD) comes from a proteome-wide binary two-hybrid map, not a
      function-establishing study, and its biological relevance to COX assembly
      is unclear. It is retained (not removed) as an experimental IPI but marked
      as over-annotated; no specific MF is proposed because COX14 acts as a
      non-catalytic scaffolding/assembly factor.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: "reference interactome map of human binary protein interactions, or 'HuRI'"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct assay (immunofluorescence-based, Human Protein Atlas) localising
      COX14 to the mitochondrion. Consistent with all other evidence.
    action: ACCEPT
    reason: >-
      COX14 is a bona fide mitochondrial protein; immunofluorescence
      localisation to the mitochondrion is correct, though non-specific relative
      to the inner-membrane sub-localisation captured elsewhere.
    supported_by:
    - reference_id: PMID:22356826
      supporting_text: "Four of the proteins (AURKAIP1-, C7orf44-, C12orf62- and PET117-GFP) co-localize with the mitochondrial marker"
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: IMP
  original_reference_id: PMID:28082314
  qualifier: involved_in
  review:
    summary: >-
      Experimental (IMP) annotation for Complex IV assembly, from the CMC1
      knockout study showing COX14 participates in an early COX1-COA3-COX14
      assembly intermediate whose destabilisation impairs COX biogenesis.
    action: ACCEPT
    reason: >-
      Strongly supported core function. The study places COX14 in an early
      COX1-containing assembly intermediate that must form before COX4/COX5a
      incorporation, directly implicating it in Complex IV assembly.
    supported_by:
    - reference_id: PMID:28082314
      supporting_text: "CMC1 stabilizes a COX1-COA3-COX14 complex before the incorporation of COX4 and"
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IDA
  original_reference_id: PMID:28082314
  qualifier: enables
  review:
    summary: >-
      Direct-assay MF annotation as a protein folding chaperone. The cited paper
      shows COX14 is part of an early COX1-COA3-COX14 assembly intermediate that
      stabilises newly synthesised COX1, but does not demonstrate a classical
      protein-folding chaperone catalytic activity for COX14 itself.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      COX14 functions as a scaffolding/regulatory assembly factor within MITRAC
      rather than as a canonical folding chaperone; the stabilisation of nascent
      COX1 is a complex-assembly effect. Assigning a 'protein folding chaperone'
      molecular function over-interprets this scaffolding role. This experimental
      IDA is retained but flagged as over-annotated rather than removed, since we
      cannot fully verify the curator's full-text rationale; the core role is
      better represented as Complex IV assembly (GO:0033617).
    supported_by:
    - reference_id: PMID:28082314
      supporting_text: "CMC1 stabilizes a COX1-COA3-COX14 complex before the incorporation of COX4 and"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomic identification of COX14 in the high-confidence
      human mitochondrial proteome (MitoCoP). Corroborates mitochondrial
      localisation.
    action: ACCEPT
    reason: >-
      Independent high-throughput evidence consistent with all other data that
      COX14 is a mitochondrial protein.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: "high-confidence human mitochondrial proteome and its dynamics in cellular context"
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IDA
  original_reference_id: PMID:27184847
  qualifier: located_in
  review:
    summary: >-
      Direct-assay (APEX fingerprinting/topology) annotation to mitochondrial
      outer membrane. This conflicts with the protein's function as an
      inner-membrane MITRAC/Complex IV assembly factor and with Reactome's
      inner-membrane placement.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The APEX study (PMID:27184847) mapped sub-mitochondrial localisation and
      membrane topology; the resulting outer-membrane assignment is at odds with
      COX14's established role engaging MT-CO1 within the inner-membrane COX
      assembly machinery, where Reactome places it. Rather than removing an
      experimental annotation whose full text we cannot fully verify, it is
      marked as over-annotated; the inner membrane (GO:0005743) is treated as the
      functionally relevant location.
    supported_by:
    - reference_id: PMID:27184847
      supporting_text: "sub-mitochondrial localization of recently identified mitochondrial"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9865350
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) annotation placing COX14 in the mitochondrial inner
      membrane as a subunit of the MITRAC complex that binds nascent MT-CO1.
      This is the functionally correct location for COX14.
    action: ACCEPT
    reason: >-
      Complex IV and its assembly intermediates reside in the inner membrane,
      and Reactome models COX14 as a MITRAC subunit engaging nascent MT-CO1
      there. This is the anatomically and functionally appropriate location and
      is used in core_functions.
    supported_by:
    - reference_id: Reactome:R-HSA-9865350
      supporting_text: "Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly Complex (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62)"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9865412
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) annotation to mitochondrial inner membrane, from a MITRAC
      assembly reaction. Duplicate location supporting COX14's inner-membrane
      residence.
    action: ACCEPT
    reason: >-
      Consistent with COX14's role in the inner-membrane MITRAC/Complex IV
      assembly pathway. Correct location.
    supported_by:
    - reference_id: Reactome:R-HSA-9865350
      supporting_text: "Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly Complex (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62)"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9865449
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) annotation to mitochondrial inner membrane, from a MITRAC
      assembly reaction. Duplicate location supporting COX14's inner-membrane
      residence.
    action: ACCEPT
    reason: >-
      Consistent with COX14's inner-membrane role in COX assembly. Correct
      location.
    supported_by:
    - reference_id: Reactome:R-HSA-9865350
      supporting_text: "Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly Complex (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62)"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9865579
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) annotation to mitochondrial inner membrane, from a MITRAC
      assembly reaction. Duplicate location supporting COX14's inner-membrane
      residence.
    action: ACCEPT
    reason: >-
      Consistent with COX14's inner-membrane role in COX assembly. Correct
      location.
    supported_by:
    - reference_id: Reactome:R-HSA-9865350
      supporting_text: "Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly Complex (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62)"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9865663
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) annotation to mitochondrial inner membrane, from a MITRAC
      assembly reaction. Duplicate location supporting COX14's inner-membrane
      residence.
    action: ACCEPT
    reason: >-
      Consistent with COX14's inner-membrane role in COX assembly. Correct
      location.
    supported_by:
    - reference_id: Reactome:R-HSA-9865350
      supporting_text: "Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly Complex (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62)"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:22356826
  qualifier: located_in
  review:
    summary: >-
      Direct-assay (GFP co-localisation with a mitochondrial marker) annotation
      localising C12orf62/COX14 to the mitochondrion.
    action: ACCEPT
    reason: >-
      Experimental live-cell imaging shows C12orf62-GFP co-localises with the
      mitochondrial marker, confirming mitochondrial localisation.
    supported_by:
    - reference_id: PMID:22356826
      supporting_text: "Four of the proteins (AURKAIP1-, C7orf44-, C12orf62- and PET117-GFP) co-localize with the mitochondrial marker"
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: TAS
  original_reference_id: PMID:22356826
  qualifier: involved_in
  review:
    summary: >-
      TAS annotation for Complex IV assembly, from the study that identified
      C12orf62 as the human COX14 ortholog and confirmed it as a COX assembly
      factor binding COX1 and regulating its translation.
    action: ACCEPT
    reason: >-
      Core function, well supported: C12orf62/COX14 is a COX assembly factor
      that binds COX1 and acts as its translation regulator, and its
      overexpression reduces COX subunit and holocomplex levels.
    supported_by:
    - reference_id: PMID:22356826
      supporting_text: "We experimentally confirm the role of C12orf62 as a COX assembly factor binding to COX1 and acting as its translation regulator"
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: IMP
  original_reference_id: PMID:22243966
  qualifier: involved_in
  review:
    summary: >-
      Experimental (IMP) annotation for Complex IV assembly from the disease
      study: a homozygous C12orf62/COX14 mutation causes a COX-assembly defect
      and specific decrease in COX1 synthesis; knockdown recapitulates the
      defect. Establishes COX14 as required for early COX assembly coupled to
      COX1 synthesis.
    action: ACCEPT
    reason: >-
      This is a defining experimental annotation for COX14's core function.
      Patient fibroblasts and siRNA knockdown both show impaired COX assembly,
      and the authors conclude COX14 coordinates the early steps of COX assembly
      with COX1 synthesis.
    supported_by:
    - reference_id: PMID:22243966
      supporting_text: "C12orf62 is required for coordination of the early steps of COX assembly with"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:22243966
  qualifier: located_in
  review:
    summary: >-
      Direct-assay annotation localising C12orf62/COX14 to mitochondria in the
      disease study.
    action: ACCEPT
    reason: >-
      Consistent with all other localisation evidence; C12orf62 is described as
      a small single-transmembrane protein that localizes to mitochondria.
    supported_by:
    - reference_id: PMID:22243966
      supporting_text: "single-transmembrane protein that localizes to mitochondria"
core_functions:
- description: >-
    Early assembly factor for mitochondrial respiratory chain Complex IV
    (cytochrome c oxidase). As a core component of the inner-membrane MITRAC
    complex, COX14 associates with newly synthesised MT-CO1 (COX1) and, with
    COA3 and other MITRAC/assembly components, couples MT-CO1 synthesis with its
    incorporation into the nascent enzyme, regulating and stabilising the early
    COX1-containing assembly intermediate. COX14 is non-catalytic and acts as a
    scaffolding/regulatory factor; no informative molecular-function term is
    assigned (GOA carries only bare protein binding and an over-interpreted
    'protein folding chaperone' term).
  directly_involved_in:
  - id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:22243966
    supporting_text: "C12orf62 is required for coordination of the early steps of COX assembly with"
  - reference_id: PMID:22356826
    supporting_text: "We experimentally confirm the role of C12orf62 as a COX assembly factor binding to COX1 and acting as its translation regulator"
  - reference_id: PMID:28082314
    supporting_text: "CMC1 stabilizes a COX1-COA3-COX14 complex before the incorporation of COX4 and"
  - reference_id: Reactome:R-HSA-9865350
    supporting_text: "Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly Complex (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62)"
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: PMID:22243966
  title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome
    c oxidase assembly, cause fatal neonatal lactic acidosis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Disease + functional study establishing COX14/C12orf62 as required for
      early COX assembly coupled to COX1 synthesis; source of the MC4DN10
      disease association and the M19I variant. PMID/title verified against the
      cached abstract.
- id: PMID:22356826
  title: Iterative orthology prediction uncovers new mitochondrial proteins and identifies
    C12orf62 as the human ortholog of COX14, a protein involved in the assembly of
    cytochrome c oxidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Identifies C12orf62 as human COX14 ortholog; experimentally confirms it
      binds COX1 and acts as its translation regulator, and localises it to
      mitochondria. Full text available and verified.
- id: PMID:27184847
  title: APEX Fingerprinting Reveals the Subcellular Localization of Proteins of Interest.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Methods paper mapping sub-mitochondrial localisation/topology; cited as
      source of an outer-membrane assignment that conflicts with COX14's
      inner-membrane MITRAC function (annotation marked over-annotated).
- id: PMID:28082314
  title: A CMC1-knockout reveals translation-independent control of human mitochondrial
    complex IV biogenesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Places COX14 in an early COX1-COA3-COX14 assembly intermediate stabilised
      by CMC1; supports Complex IV assembly role. Does not establish a genuine
      folding-chaperone MF, so the GO:0044183 annotation is over-annotated.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput HuRI binary interactome; source of a bare protein binding
      IPI (COX14-MESD). Correctly cited but only supports an uninformative MF
      term, so the annotation is marked over-annotated.
- 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: >-
      MitoCoP high-confidence mitochondrial proteome; independent HTP support
      for COX14's mitochondrial localisation.
- id: Reactome:R-HSA-9865350
  title: Nascent MT-CO1 binds to MITRAC, Mg2+, PE, CL
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction modelling COX14 as a MITRAC subunit binding nascent
      MT-CO1 in the mitochondrial inner membrane; supports both the inner-membrane
      location and the Complex IV assembly role.
- id: Reactome:R-HSA-9865412
  title: TIMM21 carries COX4, COX5A, COX6C to MT-CO1:MITRAC
  findings: []
- id: Reactome:R-HSA-9865449
  title: Metallochaperone inserts Cu2+ into MT-CO1
  findings: []
- id: Reactome:R-HSA-9865579
  title: MT-CO1 and MT-CO2 complexes associate, installing heme moieties
  findings: []
- id: Reactome:R-HSA-9865663
  title: MT-CO3, COX6A,B,7A and NDUFA4 bind to holo-MT-CO1,2 complex
  findings: []
- id: file:human/COX14/COX14-uniprot.txt
  title: UniProtKB entry Q96I36 (COX14_HUMAN)
  findings: []