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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/COX8A/COX8A-uniprot.txt Mitochondrion inner membrane |
| GO:0045277 respiratory chain complex IV | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of COX8A as part of respiratory chain complex IV (cytochrome c oxidase). This is a core, defining feature of the protein. 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. Supporting Evidence: file:human/COX8A/COX8A-uniprot.txt COX8A and COXFA4, which are encoded PMID:30030519 the intact complex-IV is a monomer containing 14 subunits |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer from the UniProt subcellular location (mitochondrion inner membrane). This is the correct, specific anatomical location of COX8A. 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. Supporting Evidence: file:human/COX8A/COX8A-uniprot.txt Mitochondrion inner membrane file:human/COX8A/COX8A-uniprot.txt Single-pass membrane protein |
| GO:0006123 mitochondrial electron transport, cytochrome c to oxygen | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: PMID:30030519 It accepts electrons from cytochrome c to reduce the oxygen to water |
| GO:0045277 respiratory chain complex IV | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO assignment of Complex IV membership, duplicating the IBA and experimental (IPI) calls for the same complex. Reason: Redundant with the IBA and ComplexPortal IPI Complex IV annotations, and correct. Duplicate complex-membership annotations from different evidence lines are acceptable. Supporting Evidence: file:human/COX8A/COX8A-uniprot.txt COX8A and COXFA4, which are encoded |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/COX8A/COX8A-uniprot.txt the active site in subunit 1, a binuclear center (BNC) formed by |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:25416956 a systematic map of ?14,000 high-quality human binary protein-protein interactions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | 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. 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). Supporting Evidence: PMID:32296183 we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI' |
| GO:0043403 skeletal muscle tissue regeneration | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/COX8A/COX8A-uniprot.txt Widely expressed |
| GO:0006119 oxidative phosphorylation | IEA GO_REF:0000041 | ACCEPT | Summary: UniPathway-based mapping to oxidative phosphorylation, the overarching energy-metabolism pathway that Complex IV (and hence COX8A) participates in. 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. Supporting Evidence: file:human/COX8A/COX8A-uniprot.txt PATHWAY: Energy metabolism; oxidative phosphorylation |
| GO:0006123 mitochondrial electron transport, cytochrome c to oxygen | NAS PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | ACCEPT | 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. Reason: Correct core biological process for a Complex IV subunit, supported by the structural characterization of the intact 14-subunit human cytochrome c oxidase. Supporting Evidence: PMID:30030519 It accepts electrons from cytochrome c to reduce the oxygen to water |
| GO:0031966 mitochondrial membrane | IDA PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | ACCEPT | 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. Reason: Consistent with the experimentally determined single-pass inner-membrane topology. Retained as a correct, slightly broader parent of GO:0005743. Supporting Evidence: PMID:30030519 freely scattered on mitochondrial inner membrane |
| GO:0045277 respiratory chain complex IV | IPI PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | ACCEPT | 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. Reason: Directly supported by structural determination of the complete human cytochrome c oxidase, which resolves COX8A as a subunit. Core, defining annotation. Supporting Evidence: PMID:30030519 the intact complex-IV is a monomer containing 14 subunits file:human/COX8A/COX8A-uniprot.txt 11 supernumerary subunits |
| GO:0045333 cellular respiration | NAS PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | ACCEPT | Summary: ComplexPortal (NAS) assignment to cellular respiration, the broad process encompassing the electron transport chain in which Complex IV operates. Reason: Correct but broad. Retained as a non-core parent of the more specific electron-transport and oxidative-phosphorylation processes. Supporting Evidence: PMID:30030519 CIV is the terminal oxidase of the electron transport chain in mitochondria |
| GO:0005743 mitochondrial inner membrane | EXP PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | ACCEPT | 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. Reason: Strong experimental support: the structure places COX8A within Complex IV embedded in the inner membrane, with a single transmembrane helix. Core localization annotation. Supporting Evidence: PMID:30030519 freely scattered on mitochondrial inner membrane file:human/COX8A/COX8A-uniprot.txt Single-pass membrane protein |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | 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. 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. Supporting Evidence: PMID:34800366 defined a human mitochondrial high-confidence proteome (MitoCoP |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-163214 | ACCEPT | 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. Reason: Correct core localization, consistent with the experimental and IEA calls for the same term. Duplicate CC annotation from Reactome is acceptable. Supporting Evidence: file:human/COX8A/COX8A-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9709406 | ACCEPT | 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. Reason: Duplicate, correct inner-membrane localization from Reactome. Consistent with all other localization evidence. Supporting Evidence: file:human/COX8A/COX8A-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865579 | ACCEPT | 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). Reason: Correct localization; this Reactome reaction explicitly names COX8A as one of the subunits joining during Complex IV assembly in the inner membrane. Supporting Evidence: Reactome:R-HSA-9865579 associating with the COX7B, COX7C, and COX8A subunits |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865663 | ACCEPT | Summary: Reactome (TAS) inner-membrane localization associated with the final Complex IV assembly step. Correct, duplicate localization annotation. Reason: Consistent, correct inner-membrane localization from Reactome assembly pathway. Acceptable duplicate of the core CC annotation. Supporting Evidence: file:human/COX8A/COX8A-uniprot.txt Mitochondrion inner membrane |
| GO:0004129 cytochrome-c oxidase activity | TAS PMID:2543673 A gene specifying subunit VIII of human cytochrome c oxidase... | MARK AS OVER ANNOTATED | 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. 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 replacements: structural molecule activity Supporting Evidence: file:human/COX8A/COX8A-uniprot.txt the active site in subunit 1, a binuclear center (BNC) formed by PMID:2543673 Subunit VIII of mammalian cytochrome c oxidase |
| GO:0006091 generation of precursor metabolites and energy | TAS PMID:2543673 A gene specifying subunit VIII of human cytochrome c oxidase... | ACCEPT | Summary: Broad traceable-author-statement process annotation reflecting Complex IV's role in energy generation via oxidative phosphorylation. Reason: Correct but high-level. Retained as a non-core broad parent of the more specific electron-transport and oxidative-phosphorylation annotations. Supporting Evidence: file:human/COX8A/COX8A-uniprot.txt the last enzyme in the |
| GO:0005198 structural molecule activity | IDA PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | NEW | 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. 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. Supporting Evidence: PMID:30030519 the intact complex-IV is a monomer containing 14 subunits file:human/COX8A/COX8A-uniprot.txt 11 supernumerary subunits |
Loading supporting content…
Download this section (compressed HTML)Q: Does COX8A incorporation contribute specifically to Complex IV assembly kinetics or stability, beyond its structural presence in the mature complex?
Experiment: 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.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)