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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:22356826 Four of the proteins (AURKAIP1-, C7orf44-, C12orf62- and PET117-GFP) co-localize with the mitochondrial marker |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:22243966 C12orf62 is required for coordination of the early steps of COX assembly with PMID:22356826 We experimentally confirm the role of C12orf62 as a COX assembly factor binding to COX1 and acting as its translation regulator |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/COX14/COX14-uniprot.txt TOPO_DOM 1..14 |
| GO:0006457 protein folding | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:28082314 CMC1 stabilizes a COX1-COA3-COX14 complex before the incorporation of COX4 and |
| 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 a high-throughput binary interactome screen (HuRI), recording a COX14 interaction with MESD (Q14696). This is an uninformative molecular-function term. 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. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions, or 'HuRI' |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Direct assay (immunofluorescence-based, Human Protein Atlas) localising COX14 to the mitochondrion. Consistent with all other evidence. 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. Supporting Evidence: PMID:22356826 Four of the proteins (AURKAIP1-, C7orf44-, C12orf62- and PET117-GFP) co-localize with the mitochondrial marker |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IMP PMID:28082314 A CMC1-knockout reveals translation-independent control of h... | ACCEPT | 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. 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. Supporting Evidence: PMID:28082314 CMC1 stabilizes a COX1-COA3-COX14 complex before the incorporation of COX4 and |
| GO:0044183 protein folding chaperone | IDA PMID:28082314 A CMC1-knockout reveals translation-independent control of h... | MARK AS OVER ANNOTATED | 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. 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). Supporting Evidence: PMID:28082314 CMC1 stabilizes a COX1-COA3-COX14 complex before the incorporation of COX4 and |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput proteomic identification of COX14 in the high-confidence human mitochondrial proteome (MitoCoP). Corroborates mitochondrial localisation. Reason: Independent high-throughput evidence consistent with all other data that COX14 is a mitochondrial protein. Supporting Evidence: PMID:34800366 high-confidence human mitochondrial proteome and its dynamics in cellular context |
| GO:0005741 mitochondrial outer membrane | IDA PMID:27184847 APEX Fingerprinting Reveals the Subcellular Localization of ... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:27184847 sub-mitochondrial localization of recently identified mitochondrial |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865350 | ACCEPT | 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. 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. Supporting Evidence: Reactome:R-HSA-9865350 Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly Complex (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62) |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865412 | ACCEPT | Summary: Reactome (TAS) annotation to mitochondrial inner membrane, from a MITRAC assembly reaction. Duplicate location supporting COX14's inner-membrane residence. Reason: Consistent with COX14's role in the inner-membrane MITRAC/Complex IV assembly pathway. Correct location. Supporting Evidence: Reactome:R-HSA-9865350 Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly Complex (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62) |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865449 | ACCEPT | Summary: Reactome (TAS) annotation to mitochondrial inner membrane, from a MITRAC assembly reaction. Duplicate location supporting COX14's inner-membrane residence. Reason: Consistent with COX14's inner-membrane role in COX assembly. Correct location. Supporting Evidence: Reactome:R-HSA-9865350 Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly Complex (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62) |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865579 | ACCEPT | Summary: Reactome (TAS) annotation to mitochondrial inner membrane, from a MITRAC assembly reaction. Duplicate location supporting COX14's inner-membrane residence. Reason: Consistent with COX14's inner-membrane role in COX assembly. Correct location. Supporting Evidence: Reactome:R-HSA-9865350 Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly Complex (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62) |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865663 | ACCEPT | Summary: Reactome (TAS) annotation to mitochondrial inner membrane, from a MITRAC assembly reaction. Duplicate location supporting COX14's inner-membrane residence. Reason: Consistent with COX14's inner-membrane role in COX assembly. Correct location. Supporting Evidence: Reactome:R-HSA-9865350 Nascent MT-CO1 binds to Mitochondrial Translation Regulation and Assembly Complex (MITRAC), consisting of the subunits CMC1 (C3orf68), COX14 (C12orf62) |
| GO:0005739 mitochondrion | IDA PMID:22356826 Iterative orthology prediction uncovers new mitochondrial pr... | ACCEPT | Summary: Direct-assay (GFP co-localisation with a mitochondrial marker) annotation localising C12orf62/COX14 to the mitochondrion. Reason: Experimental live-cell imaging shows C12orf62-GFP co-localises with the mitochondrial marker, confirming mitochondrial localisation. Supporting Evidence: PMID:22356826 Four of the proteins (AURKAIP1-, C7orf44-, C12orf62- and PET117-GFP) co-localize with the mitochondrial marker |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | TAS PMID:22356826 Iterative orthology prediction uncovers new mitochondrial pr... | ACCEPT | 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. 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. Supporting Evidence: PMID:22356826 We experimentally confirm the role of C12orf62 as a COX assembly factor binding to COX1 and acting as its translation regulator |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IMP PMID:22243966 Mutations in C12orf62, a factor that couples COX I synthesis... | ACCEPT | 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. 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. Supporting Evidence: PMID:22243966 C12orf62 is required for coordination of the early steps of COX assembly with |
| GO:0005739 mitochondrion | IDA PMID:22243966 Mutations in C12orf62, a factor that couples COX I synthesis... | ACCEPT | Summary: Direct-assay annotation localising C12orf62/COX14 to mitochondria in the disease study. Reason: Consistent with all other localisation evidence; C12orf62 is described as a small single-transmembrane protein that localizes to mitochondria. Supporting Evidence: PMID:22243966 single-transmembrane protein that localizes to mitochondria |
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