id: P10176
gene_symbol: COX8A
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  COX8A encodes cytochrome c oxidase subunit 8A, a small (69-aa precursor,
  44-aa mature) nuclear-encoded, single-pass structural subunit of mitochondrial
  respiratory chain Complex IV (cytochrome c oxidase, the terminal enzyme of the
  electron transport chain). It is the ubiquitously expressed COX8 isoform and,
  in primates, the only COX VIII form. Complex IV has a catalytic core of three
  mitochondrially encoded subunits (MT-CO1, MT-CO2, MT-CO3) that carry the redox
  centers (heme a/a3, Cu_A, Cu_B) surrounded by eleven nuclear-encoded
  supernumerary subunits, of which COX8A is the smallest. COX8A is non-catalytic:
  it does not itself perform cytochrome c oxidase chemistry but contributes to the
  structural integrity, assembly, and stability of the complex, which reduces
  molecular oxygen to water using electrons from cytochrome c and helps generate
  the transmembrane proton-motive force that drives ATP synthesis. The protein is
  anchored in the mitochondrial inner membrane by a single transmembrane helix.
  Loss-of-function variants cause mitochondrial complex IV deficiency, nuclear
  type 15 (MC4DN15), an autosomal recessive Leigh-like syndrome with epilepsy.
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) assignment of mitochondrial localization. Correct but
      less specific than the mitochondrial inner membrane where COX8A actually
      resides as a Complex IV subunit.
    action: ACCEPT
    reason: >-
      COX8A is a bona fide mitochondrial protein and a subunit of the inner-membrane
      Complex IV. The IBA call is accurate; it is retained as a broad, non-core
      parent of the more informative GO:0005743 localization.
    supported_by:
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "Mitochondrion inner membrane"
- term:
    id: GO:0045277
    label: respiratory chain complex IV
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      Phylogenetic assignment of COX8A as part of respiratory chain complex IV
      (cytochrome c oxidase). This is a core, defining feature of the protein.
    action: ACCEPT
    reason: >-
      Structural and biochemical evidence confirm COX8A is one of the eleven
      nuclear-encoded supernumerary subunits of the 14-subunit human Complex IV.
      GO:0045277 is the current (non-obsolete) term for this complex.
    supported_by:
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "COX8A and COXFA4, which are encoded"
    - reference_id: PMID:30030519
      supporting_text: "the intact complex-IV is a monomer containing 14 subunits"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic transfer from the UniProt subcellular location (mitochondrion
      inner membrane). This is the correct, specific anatomical location of COX8A.
    action: ACCEPT
    reason: >-
      COX8A is a single-pass inner-membrane protein, consistent with its role as
      a membrane-embedded Complex IV subunit. The subcellular-location mapping is
      accurate and matches experimental structural data.
    supported_by:
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "Mitochondrion inner membrane"
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "Single-pass membrane protein"
- term:
    id: GO:0006123
    label: mitochondrial electron transport, cytochrome c to oxygen
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO mapping of the COX8 domain to the cytochrome-c-to-oxygen
      electron-transport step. This is the core biological process of Complex IV
      and COX8A participates as a structural subunit.
    action: ACCEPT
    reason: >-
      COX8A is part of Complex IV, which transfers electrons from cytochrome c to
      molecular oxygen. The InterPro-based process assignment is biologically
      correct for a Complex IV subunit.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: "It accepts electrons from cytochrome c to reduce the oxygen to water"
- term:
    id: GO:0045277
    label: respiratory chain complex IV
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: >-
      InterPro2GO assignment of Complex IV membership, duplicating the IBA and
      experimental (IPI) calls for the same complex.
    action: ACCEPT
    reason: >-
      Redundant with the IBA and ComplexPortal IPI Complex IV annotations, and
      correct. Duplicate complex-membership annotations from different evidence
      lines are acceptable.
    supported_by:
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "COX8A and COXFA4, which are encoded"
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      Logical inference chained from the cytochrome-c oxidase molecular function
      (GO:0004129) to proton transmembrane transport. Complex IV does pump protons,
      but this activity resides in the catalytic mtDNA-encoded core (MT-CO1),
      not in the non-catalytic supernumerary subunit COX8A.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This process is inferred from a molecular-function assignment (cytochrome-c
      oxidase activity) that is itself an over-annotation for this structural
      subunit. Proton pumping is performed by the catalytic core, so attributing
      proton transmembrane transport directly to COX8A over-states its role. It is
      not wrong at the whole-complex level but is not a core function of COX8A.
    supported_by:
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "the active site in subunit 1, a binuclear center (BNC) formed by"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Bare 'protein binding' from a proteome-scale binary (Y2H) interactome
      screen. The recorded partner (NPM1, a nucleolar protein) is not a Complex IV
      component and is not a plausible physiological partner of a buried
      inner-membrane oxidase subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 is uninformative and provides no functional insight. The
      interaction comes from a high-throughput binary map, not a directed study of
      COX8A function, and the partner is inconsistent with COX8A's biology. Per
      curation policy this bare-binding IPI is marked as over-annotated rather than
      removed.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: "a systematic map of ?14,000 high-quality human binary protein-protein interactions"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare 'protein binding' from the HuRI all-by-all binary interactome map.
      Reported partners (MAGEA4, EDDM3B, BATF) are not Complex IV subunits or
      assembly factors.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative term derived from a systematic Y2H reference map rather than a
      focused functional study; the interactors are not consistent with COX8A's
      role as an inner-membrane Complex IV subunit. Marked as over-annotated per
      policy (not removed).
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: "we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'"
- term:
    id: GO:0043403
    label: skeletal muscle tissue regeneration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer of a manual annotation from the rat ortholog (P80433)
      via Ensembl Compara. COX8A is a ubiquitously expressed housekeeping OXPHOS
      subunit; there is no direct human evidence for a dedicated role in skeletal
      muscle tissue regeneration.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This is an orthology-based electronic annotation to a specialized tissue
      process that does not reflect a demonstrated COX8A-specific function in human.
      It represents over-annotation of a general respiratory-chain subunit to a
      narrow developmental/regenerative process and is not core.
    supported_by:
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "Widely expressed"
- term:
    id: GO:0006119
    label: oxidative phosphorylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-based mapping to oxidative phosphorylation, the overarching
      energy-metabolism pathway that Complex IV (and hence COX8A) participates in.
    action: ACCEPT
    reason: >-
      Complex IV is a core component of oxidative phosphorylation; COX8A's
      participation as a subunit makes this a correct, if broad, process
      annotation. Retained as non-core parent of the more specific GO:0006123.
    supported_by:
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "PATHWAY: Energy metabolism; oxidative phosphorylation"
- term:
    id: GO:0006123
    label: mitochondrial electron transport, cytochrome c to oxygen
  evidence_type: NAS
  original_reference_id: PMID:30030519
  qualifier: involved_in
  review:
    summary: >-
      ComplexPortal (NAS) assignment of the cytochrome-c-to-oxygen electron
      transport step, the defining biological process of Complex IV. Duplicates
      the InterPro2GO IEA call for the same term.
    action: ACCEPT
    reason: >-
      Correct core biological process for a Complex IV subunit, supported by the
      structural characterization of the intact 14-subunit human cytochrome c
      oxidase.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: "It accepts electrons from cytochrome c to reduce the oxygen to water"
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IDA
  original_reference_id: PMID:30030519
  qualifier: located_in
  review:
    summary: >-
      Direct (ComplexPortal IDA) localization to mitochondrial membrane, based on
      the cryo-EM structure showing COX8A embedded in Complex IV. Correct but less
      specific than mitochondrial inner membrane.
    action: ACCEPT
    reason: >-
      Consistent with the experimentally determined single-pass inner-membrane
      topology. Retained as a correct, slightly broader parent of GO:0005743.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: "freely scattered on mitochondrial inner membrane"
- term:
    id: GO:0045277
    label: respiratory chain complex IV
  evidence_type: IPI
  original_reference_id: PMID:30030519
  qualifier: part_of
  review:
    summary: >-
      ComplexPortal experimental (IPI) assignment of COX8A as part of respiratory
      chain complex IV, based on the intact 14-subunit cryo-EM structure. This is
      the strongest, most direct evidence for the core complex-membership call.
    action: ACCEPT
    reason: >-
      Directly supported by structural determination of the complete human
      cytochrome c oxidase, which resolves COX8A as a subunit. Core, defining
      annotation.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: "the intact complex-IV is a monomer containing 14 subunits"
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "11 supernumerary subunits"
- term:
    id: GO:0045333
    label: cellular respiration
  evidence_type: NAS
  original_reference_id: PMID:30030519
  qualifier: involved_in
  review:
    summary: >-
      ComplexPortal (NAS) assignment to cellular respiration, the broad process
      encompassing the electron transport chain in which Complex IV operates.
    action: ACCEPT
    reason: >-
      Correct but broad. Retained as a non-core parent of the more specific
      electron-transport and oxidative-phosphorylation processes.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: "CIV is the terminal oxidase of the electron transport chain in mitochondria"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: EXP
  original_reference_id: PMID:30030519
  qualifier: located_in
  review:
    summary: >-
      Experimental localization to the mitochondrial inner membrane from the
      cryo-EM structure of intact human cytochrome c oxidase. This is the core,
      specific anatomical location of COX8A.
    action: ACCEPT
    reason: >-
      Strong experimental support: the structure places COX8A within Complex IV
      embedded in the inner membrane, with a single transmembrane helix. Core
      localization annotation.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: "freely scattered on mitochondrial inner membrane"
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "Single-pass membrane protein"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics assignment of mitochondrial localization from the
      MitoCoP high-confidence human mitochondrial proteome. Correct but broad
      relative to the inner-membrane localization.
    action: ACCEPT
    reason: >-
      COX8A is a validated member of the high-confidence mitochondrial proteome.
      The call is accurate; retained as a broad, non-core parent of GO:0005743.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: "defined a human mitochondrial high-confidence proteome (MitoCoP"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-163214
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author-statement localization to the mitochondrial inner
      membrane, in the context of electron transfer from cytochrome c to oxygen
      by Complex IV.
    action: ACCEPT
    reason: >-
      Correct core localization, consistent with the experimental and IEA calls
      for the same term. Duplicate CC annotation from Reactome is acceptable.
    supported_by:
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "Mitochondrion inner membrane"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9709406
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) inner-membrane localization associated with the CO-binding
      reaction of cytochrome c oxidase. Correct localization for COX8A as a
      Complex IV subunit.
    action: ACCEPT
    reason: >-
      Duplicate, correct inner-membrane localization from Reactome. Consistent
      with all other localization evidence.
    supported_by:
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "Mitochondrion inner membrane"
- 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) inner-membrane localization tied to the Complex IV assembly
      step at which COX8A is incorporated (association of MT-CO1/MT-CO2 with
      COX7B, COX7C, and COX8A).
    action: ACCEPT
    reason: >-
      Correct localization; this Reactome reaction explicitly names COX8A as one
      of the subunits joining during Complex IV assembly in the inner membrane.
    supported_by:
    - reference_id: Reactome:R-HSA-9865579
      supporting_text: "associating with the COX7B, COX7C, and COX8A subunits"
- 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) inner-membrane localization associated with the final
      Complex IV assembly step. Correct, duplicate localization annotation.
    action: ACCEPT
    reason: >-
      Consistent, correct inner-membrane localization from Reactome assembly
      pathway. Acceptable duplicate of the core CC annotation.
    supported_by:
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "Mitochondrion inner membrane"
- term:
    id: GO:0004129
    label: cytochrome-c oxidase activity
  evidence_type: TAS
  original_reference_id: PMID:2543673
  qualifier: enables
  review:
    summary: >-
      Traceable-author-statement assignment of cytochrome-c oxidase activity to
      COX8A. However, COX8A is a non-catalytic, nuclear-encoded supernumerary
      subunit; the catalytic redox chemistry is performed by the mtDNA-encoded core
      subunits MT-CO1 and MT-CO2. The cited paper (PMID:2543673) is a gene-mapping
      and cDNA-characterization study, not a demonstration that COX8A itself
      catalyzes oxidase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Attributing the enzymatic cytochrome-c oxidase activity directly to a
      structural subunit over-states its molecular function. The activity is a
      property of the assembled complex driven by the catalytic core, not of COX8A.
      A more accurate molecular function is structural molecule activity
      (GO:0005198) contributing to the complex's cytochrome-c oxidase activity. Not
      removed, because the whole-complex activity is real and the evidence line is
      author-attested.
    proposed_replacement_terms:
    - id: GO:0005198
      label: structural molecule activity
    supported_by:
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "the active site in subunit 1, a binuclear center (BNC) formed by"
    - reference_id: PMID:2543673
      supporting_text: "Subunit VIII of mammalian cytochrome c oxidase"
- term:
    id: GO:0006091
    label: generation of precursor metabolites and energy
  evidence_type: TAS
  original_reference_id: PMID:2543673
  qualifier: involved_in
  review:
    summary: >-
      Broad traceable-author-statement process annotation reflecting Complex IV's
      role in energy generation via oxidative phosphorylation.
    action: ACCEPT
    reason: >-
      Correct but high-level. Retained as a non-core broad parent of the more
      specific electron-transport and oxidative-phosphorylation annotations.
    supported_by:
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "the last enzyme in the"
- term:
    id: GO:0005198
    label: structural molecule activity
  evidence_type: IDA
  original_reference_id: PMID:30030519
  qualifier: enables
  review:
    summary: >-
      Proposed molecular function for COX8A as a non-catalytic supernumerary
      subunit: it contributes to the structural integrity of Complex IV rather
      than performing catalysis. Supported by the cryo-EM structure resolving
      COX8A as one of the 14 subunits of the intact human cytochrome c oxidase.
    action: NEW
    reason: >-
      This replaces the over-annotated cytochrome-c oxidase activity (GO:0004129)
      with a molecular function appropriate for a structural membrane subunit.
      COX8A is embedded in Complex IV via a single transmembrane helix and adds no
      catalytic residues, so structural molecule activity best captures its role.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: "the intact complex-IV is a monomer containing 14 subunits"
    - reference_id: file:human/COX8A/COX8A-uniprot.txt
      supporting_text: "11 supernumerary subunits"
core_functions:
- description: >-
    Non-catalytic structural subunit that contributes to the assembly and
    structural integrity of mitochondrial respiratory chain Complex IV
    (cytochrome c oxidase), the terminal enzyme of the electron transport chain.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  supported_by:
  - reference_id: PMID:30030519
    supporting_text: "the intact complex-IV is a monomer containing 14 subunits"
  - reference_id: file:human/COX8A/COX8A-uniprot.txt
    supporting_text: "11 supernumerary subunits"
- description: >-
    As a subunit of Complex IV, participates in the transfer of electrons from
    cytochrome c to molecular oxygen in the mitochondrial inner membrane, the
    reaction that reduces O2 to water during oxidative phosphorylation.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  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
  supported_by:
  - reference_id: PMID:30030519
    supporting_text: "It accepts electrons from cytochrome c to reduce the oxygen to water"
  - reference_id: file:human/COX8A/COX8A-uniprot.txt
    supporting_text: "Mitochondrion inner membrane"
proposed_new_terms: []
suggested_questions:
- question: >-
    Does COX8A incorporation contribute specifically to Complex IV assembly
    kinetics or stability, beyond its structural presence in the mature complex?
suggested_experiments:
- description: >-
    Quantitative assembly assays (BN-PAGE / complexome profiling) in COX8A-null
    versus wild-type cells to determine at which Complex IV assembly intermediate
    COX8A loss stalls, correlating with the reduced Complex IV activity seen in
    MC4DN15 patients.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  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: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: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: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput binary (Y2H) interactome screen; source of a bare
      'protein binding' IPI (partner NPM1). Correctly cited but not informative
      about COX8A function.
- id: PMID:2543673
  title: A gene specifying subunit VIII of human cytochrome c oxidase is localized
    to chromosome 11 and is expressed in both muscle and non-muscle tissues.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Original cDNA/gene-mapping paper for human COX VIII (COX8A); establishes
      identity and ubiquitous expression, but does not demonstrate catalytic
      activity for the subunit itself (basis for over-annotating GO:0004129).
- id: PMID:30030519
  title: Structure of the intact 14-subunit human cytochrome c oxidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cryo-EM structure resolving COX8A as a subunit of the intact 14-subunit
      human Complex IV; strongest evidence for complex membership and
      inner-membrane localization.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI all-by-all binary interactome; source of bare 'protein binding' IPIs
      to non-CIV partners (MAGEA4, EDDM3B, BATF). Correctly cited, not
      functionally informative.
- 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; supports mitochondrial
      localization of COX8A.
- 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-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/COX8A/COX8A-uniprot.txt
  title: UniProtKB entry P10176 (COX8A_HUMAN)
  findings: []