NDUFA6

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0045271 respiratory chain complex I	IBA GO_REF:0000033	ACCEPT	Summary: NDUFA6 is a bona fide structural subunit of respiratory chain Complex I. Membership is established biochemically and structurally (immunopurified complex, cryo-EM, knockout complexome profiling) and is well conserved, so the phylogenetic (IBA) inference is correct. This is a core cellular-component annotation. Reason: The PAINT node placing complex I membership on this family is confirmed for the human protein itself by immunopurification/MS (PMID:12611891), assembly-intermediate tracing (PMID:17209039), knockout complexome profiling (PMID:27626371) and cryo-EM subunit assignment (PMID:28844695). NDUFA6 appearing among the descendant evidences that grounded the node is expected rather than circular, and no human-specific loss or divergence argues against the placement. Supporting Evidence: file:human/NDUFA6/NDUFA6-uniprot.txt Accessory subunit of the mitochondrial membrane respiratory
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Correct localization. NDUFA6 is a peripheral membrane protein on the matrix side of the mitochondrial inner membrane. Consistent with UniProt subcellular location and with the IDA annotation to the same term. Correct but less specific / redundant with the Complex I membership annotation. Reason: Correct, but the same compartment is asserted by an experimental IDA row and by the Complex I membership annotations, which locate NDUFA6 more precisely. Kept as consistent background rather than as the annotation of record. Supporting Evidence: file:human/NDUFA6/NDUFA6-uniprot.txt Mitochondrion inner membrane
GO:0045271 respiratory chain complex I	IEA GO_REF:0000120	ACCEPT	Summary: Correct Complex I membership, redundant with the experimental (IPI/IDA) and IBA annotations to the same term. Electronic inference from an orthologue/InterPro is appropriate here. Reason: Complex I membership is the central structural fact about NDUFA6 and is independently established by four experimental annotations. The electronic call agrees with all of them, so it is accepted rather than demoted; the redundancy is harmless because the claim is not in doubt.
GO:1902600 proton transmembrane transport	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: This term is inferred electronically from the molecular-function annotation GO:0008137 (NADH dehydrogenase (ubiquinone) activity). Proton translocation is a whole-complex property driven by the core membrane-arm subunits; NDUFA6 is a non-catalytic accessory subunit of the peripheral arm and is "believed to be not involved in catalysis". As a downstream inference from an over-attributed MF, it describes the holoenzyme rather than NDUFA6's direct role. Reason: A logical inter-ontology inference whose premise is the GO:0008137 MF annotation that this review marks as an over-annotation for NDUFA6. Proton translocation is performed by the antiporter-like membrane-arm core subunits (ND2/ND4/ND5); NDUFA6 is a peripheral matrix-arm Q-module subunit that UniProt states is not involved in catalysis. It is retained as a true statement about the holoenzyme, not about NDUFA6. Supporting Evidence: file:human/NDUFA6/NDUFA6-uniprot.txt chain NADH dehydrogenase (Complex I), that is believed to be not
GO:0005743 mitochondrial inner membrane	IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ...	KEEP AS NON CORE	Summary: Direct experimental (cryo-EM of the human respiratory megacomplex I2III2IV2) localization of NDUFA6 to the mitochondrial inner membrane as part of Complex I. Correct; a supporting location annotation. Reason: Cryo-EM of the intact megacomplex places NDUFA6 in the membrane-embedded complex by direct observation, which is sound. It is demoted only because the same paper supplies the Complex I membership annotation, a more informative statement of the same observation, and because UniProt localizes NDUFA6 more precisely to the matrix face of the inner membrane. Supporting Evidence: PMID:28844695 The structure not only reveals the precise assignment of individual subunits of
GO:0009060 aerobic respiration	NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-...	KEEP AS NON CORE	Summary: Aerobic respiration is the high-level process served by the whole OXPHOS system. NDUFA6 contributes to it only as a structural subunit of Complex I; this term is broader than NDUFA6's specific role and is better captured by the Complex I assembly and NADH-to-ubiquinone electron transport annotations. Retained as valid but non-core. Reason: The cited source is a review stating that supernumerary subunits serve assembly, regulation and stability roles; it demonstrates no step of aerobic respiration performed by NDUFA6. The annotation is true of the OXPHOS system NDUFA6 belongs to, so it is kept as context and excluded from the core functions. Supporting Evidence: PMID:30030361 supernumerary' subunits that play essential roles in assembly, regulation
GO:0042776 proton motive force-driven mitochondrial ATP synthesis	NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-...	MARK AS OVER ANNOTATED	Summary: ATP synthesis is carried out by Complex V, not Complex I. Complex I contributes upstream by generating the proton-motive force, and NDUFA6 contributes only as a structural subunit of Complex I. This term is well removed from NDUFA6's direct function and represents a system-level over-attribution rather than the gene's specific role. Reason: The entity that performs proton-motive-force-driven ATP synthesis is Complex V. Complex I contributes only upstream, by pumping protons, and NDUFA6 contributes to Complex I only structurally - so the claim is two steps removed from anything NDUFA6 does. The cited reference is a general OXPHOS assembly review that asserts nothing specific to NDUFA6 here. Supporting Evidence: PMID:30030361 The assembly of the five oxidative phosphorylation system (OXPHOS) complexes in
GO:0045271 respiratory chain complex I	IPI PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ...	ACCEPT	Summary: Direct physical-interaction (cryo-EM) evidence that NDUFA6 is a subunit of Complex I, with individual subunits assigned in the human megacomplex structure. Strongly supported core cellular-component annotation. Reason: The megacomplex structure resolves 140 subunits and assigns them individually, which is direct physical evidence that NDUFA6 is a constituent of the assembled complex rather than a transient interactor. Accepted as core. Supporting Evidence: PMID:28844695 chain megacomplex-I2III2IV2 (MCI2III2IV2) with 140 subunits and a subset of
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	KEEP AS NON CORE	Summary: High-throughput proteomic detection of NDUFA6 in the mitochondrion. Correct but less specific than the mitochondrial inner membrane / Complex I annotations. Reason: MitoCoP is a quantitatively filtered high-confidence mitochondrial proteome, so inclusion is trustworthy evidence of mitochondrial residence; but an organelle-level proteomic inventory cannot resolve submitochondrial compartment, so it can only support the parent term. Kept as coarser corroboration. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)
GO:0045271 respiratory chain complex I	IDA PMID:12611891 The subunit composition of the human NADH dehydrogenase obta...	ACCEPT	Summary: Direct experimental membership: one-step immunopurification of human NADH dehydrogenase (Complex I) identified NDUFA6 among the resolved subunits by mass spectrometry. Core cellular-component annotation. Reason: One-step immunocapture of the intact complex followed by MALDI-TOF peptide mass fingerprinting and LC-MS/MS resolved 42 polypeptides, NDUFA6 among them. Co-purification with the immunoisolated holoenzyme is direct evidence of subunit status, and the authors note concordance with independently purified bovine Complex I. Supporting Evidence: PMID:12611891 we can resolve and identify the human
GO:0045271 respiratory chain complex I	IDA PMID:17209039 Identification of mitochondrial complex I assembly intermedi...	ACCEPT	Summary: NDUFA6 identified as a Complex I subunit during analysis of assembly intermediates (traced via tagged NDUFS3). Direct evidence for Complex I membership; core CC annotation, redundant with the other IDA/IPI membership calls. Reason: An inducible NDUFS3-GFP system resolved six distinct assembly subcomplexes on blue-native blots, distinguished from breakdown products by differential solubilization and heat treatment; composition analysis of those subcomplexes is what places NDUFA6 in the complex. Co-assembly with a traced core subunit is direct evidence of membership. Supporting Evidence: PMID:17209039 NDUFS3-GFP-containing subcomplexes gradually appeared on a blue native Western
GO:0045271 respiratory chain complex I	IDA PMID:27626371 Accessory subunits are integral for assembly and function of...	ACCEPT	Summary: Gene-editing/complexome study establishing accessory subunits (including NDUFA6) as integral subunits of human Complex I. Direct experimental membership; core CC annotation and the basis for the UniProt FUNCTION statement. Reason: Gene-edited knockout lines were made for every accessory subunit and profiled by quantitative proteomics, which both confirms NDUFA6 as a constituent and assigns it to a structural module through the destabilization pattern of its neighbours. This is the study UniProt cites for the FUNCTION statement. Supporting Evidence: PMID:27626371 Accessory subunits are integral for assembly and function of human mitochondrial PMID:27626371 Here we use gene editing to generate human knockout
GO:0045271 respiratory chain complex I	NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox...	ACCEPT	Summary: Author statement (cDNA characterization of nuclear-encoded Complex I subunits) that NDUFA6/B14 is a Complex I subunit. Correct, though weaker (NAS) than the experimental membership annotations to the same term. Reason: The paper completed the cDNA inventory of the 41 known human Complex I subunits, NDUFA6/B14 among them, so its assertion of subunit identity is well grounded even though the evidence code is NAS. It agrees with four experimental annotations to the same term and is accepted on that basis. Supporting Evidence: PMID:9878551 Human complex I appears to consist of 41 subunits of which
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-163217	KEEP AS NON CORE	Summary: Reactome-derived location annotation (Complex I oxidises NADH to NAD+). Correct localization; one of several redundant Reactome TAS annotations to the same term. Reason: Reactome places the whole Complex I holoenzyme, and hence each of its subunits, in the inner membrane; this row states a property of the complex rather than an independent observation of NDUFA6, and the same compartment is already carried by an experimental IDA. Kept as consistent corroboration. Reactome entries have no primary-literature snippet, so the cached reaction record is cited instead. Supporting Evidence: Reactome:R-HSA-163217 the HP arm lying within the inner mitochondrial membrane
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-6799178	KEEP AS NON CORE	Summary: Reactome Complex I biogenesis reaction. Correct inner-membrane localization; redundant with the other inner-membrane annotations. Reason: Reactome places the whole Complex I holoenzyme, and hence each of its subunits, in the inner membrane; this row states a property of the complex rather than an independent observation of NDUFA6, and the same compartment is already carried by an experimental IDA. Kept as consistent corroboration. Reactome entries have no primary-literature snippet, so the cached reaction record is cited instead. Supporting Evidence: Reactome:R-HSA-6799178 anchored to the inner mitochondrial membrane by Intermediate
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-6799179	KEEP AS NON CORE	Summary: Reactome Complex I biogenesis reaction. Correct inner-membrane localization; redundant with the other inner-membrane annotations. Reason: Reactome places the whole Complex I holoenzyme, and hence each of its subunits, in the inner membrane; this row states a property of the complex rather than an independent observation of NDUFA6, and the same compartment is already carried by an experimental IDA. Kept as consistent corroboration. Reactome entries have no primary-literature snippet, so the cached reaction record is cited instead. Supporting Evidence: Reactome:R-HSA-6799179 Subunits NDUFA12, NDUFS1, 4, 6, NDUFV1, 2 and 3 with the assembly factor
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-6799191	KEEP AS NON CORE	Summary: Reactome Complex I biogenesis reaction. Correct inner-membrane localization; redundant with the other inner-membrane annotations. Reason: Reactome places the whole Complex I holoenzyme, and hence each of its subunits, in the inner membrane; this row states a property of the complex rather than an independent observation of NDUFA6, and the same compartment is already carried by an experimental IDA. Kept as consistent corroboration. Reactome entries have no primary-literature snippet, so the cached reaction record is cited instead. Supporting Evidence: Reactome:R-HSA-6799191 to the inner mitochondrial membrane by NADH-ubiquinone oxidoreductase chain 1
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-6799196	KEEP AS NON CORE	Summary: Reactome Complex I biogenesis reaction. Correct inner-membrane localization; redundant with the other inner-membrane annotations. Reason: Reactome places the whole Complex I holoenzyme, and hence each of its subunits, in the inner membrane; this row states a property of the complex rather than an independent observation of NDUFA6, and the same compartment is already carried by an experimental IDA. Kept as consistent corroboration. Reactome entries have no primary-literature snippet, so the cached reaction record is cited instead. Supporting Evidence: Reactome:R-HSA-6799196 The MCIA complex, NDUFAF2-7 all dissociate from the 980kDa complex
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-6799197	KEEP AS NON CORE	Summary: Reactome Complex I biogenesis reaction. Correct inner-membrane localization; redundant with the other inner-membrane annotations. Reason: Reactome places the whole Complex I holoenzyme, and hence each of its subunits, in the inner membrane; this row states a property of the complex rather than an independent observation of NDUFA6, and the same compartment is already carried by an experimental IDA. Kept as consistent corroboration. Reactome entries have no primary-literature snippet, so the cached reaction record is cited instead. Supporting Evidence: Reactome:R-HSA-6799197 Distal components of the membrane arm MT-ND4 and 5 associate with the 550kDa
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-6799202	KEEP AS NON CORE	Summary: Reactome Complex I biogenesis reaction. Correct inner-membrane localization; redundant with the other inner-membrane annotations. Reason: Reactome places the whole Complex I holoenzyme, and hence each of its subunits, in the inner membrane; this row states a property of the complex rather than an independent observation of NDUFA6, and the same compartment is already carried by an experimental IDA. Kept as consistent corroboration. Reactome entries have no primary-literature snippet, so the cached reaction record is cited instead. Supporting Evidence: Reactome:R-HSA-6799202 The 315kDa and 370kDa subcomplexes associate to form a 550kDa complex
GO:0032981 mitochondrial respiratory chain complex I assembly	IMP PMID:30245030 Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-O...	ACCEPT	Summary: Strong experimental (IMP) evidence: bi-allelic NDUFA6 variants in patients cause an isolated Complex I assembly defect, with reduced fully assembled Complex I and concomitant loss of other Q-module subunits, rescued by re-expression. This is a core biological-process annotation for NDUFA6. Reason: This is the strongest evidence in the record and the one that distinguishes NDUFA6 from a merely co-purifying subunit: four unrelated children with bi-allelic NDUFA6 variants, complexome profiling showing reduced incorporated NDUFA6 together with loss of the other Q-module subunits NDUFAB1, NDUFA7 and NDUFA12, and normalization of Complex I on lentiviral re-expression. NDUFA6 does part of the work of assembly - it holds the Q-module together - rather than merely being required for it. Supporting Evidence: PMID:30245030 revealed a reduction of fully assembled complex I levels, whereas all other OXPHOS complexes were unaffected PMID:30245030 NDUFA6 is one of 27 accessory subunits that have been shown to be essential for complex I assembly and activity PMID:30245030 concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and PMID:30245030 Lentiviral transduction of subjects' fibroblasts showed normalization
GO:0006120 mitochondrial electron transport, NADH to ubiquinone	NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox...	ACCEPT	Summary: This is the process performed by Complex I, of which NDUFA6 is a structural subunit required for assembly and activity. NDUFA6 does not itself catalyze electron transfer, but as a Q-module structural subunit it is genuinely required for the complex to carry out this process, so it is retained as a core process annotation for the gene. Reason: NDUFA6 does not catalyse any step of electron transfer - the flavin and Fe-S chain belong to the NDUFV/NDUFS core subunits. It nevertheless does part of the work of the process in the sense GO requires: it is a structural constituent of the Q-module that houses the ubiquinone-reduction site, and its loss collapses that module and abolishes assembled Complex I. Retained as a core process on that basis, with the catalytic activity itself represented as contributes_to rather than enables. Supporting Evidence: PMID:9878551 function is the transport of electrons from NADH to ubiquinone, which is
GO:0008137 NADH dehydrogenase (ubiquinone) activity	NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox...	MARK AS OVER ANNOTATED	Summary: This is the catalytic activity of the Complex I holoenzyme, contributed by the 14 conserved core subunits. NDUFA6 is a non-catalytic accessory subunit "believed to be not involved in catalysis"; the cited paper is a cDNA-characterization study that does not demonstrate any catalytic activity of NDUFA6. Directly enabling this MF is an over-annotation. The complex-level activity is better represented via contributes_to_molecular_function in core_functions, with GO:0005198 as NDUFA6's direct MF. Reason: PMID:9878551 reports cDNA sequences for eight previously uncharacterized nuclear-encoded subunits; it assays no enzymatic activity of any of them, so the MF assignment reflects the name of the parent enzyme rather than a measurement. The redox chemistry requires FMN and the Fe-S cluster chain carried by the core subunits, which NDUFA6 does not possess, and UniProt states outright that it is believed not to be involved in catalysis. The right representation is contributes_to GO:0008137 with a structural molecule activity MF, as core_functions records. Proposed replacements: structural molecule activity Supporting Evidence: file:human/NDUFA6/NDUFA6-uniprot.txt chain NADH dehydrogenase (Complex I), that is believed to be not PMID:9878551 Here we report the cDNA sequences of the hitherto
GO:0031966 mitochondrial membrane	IDA PMID:17209039 Identification of mitochondrial complex I assembly intermedi...	KEEP AS NON CORE	Summary: Direct localization to the mitochondrial membrane. Correct but less specific than the mitochondrial inner membrane / Complex I annotations, which capture the precise location. Reason: Correct but strictly less informative: GO:0031966 is an ancestor of GO:0005743, which NDUFA6 already carries with experimental support, and UniProt specifies the matrix face of the inner membrane. Retained as consistent, non-core. Supporting Evidence: PMID:17209039 Biogenesis of human mitochondrial complex I (CI) requires the coordinated
GO:0008137 NADH dehydrogenase (ubiquinone) activity	TAS PMID:9345899 In situ hybridisation mapping of genomic clones for five hum...	MARK AS OVER ANNOTATED	Summary: As with the NAS annotation to the same term, this attributes the holoenzyme's catalytic activity directly to NDUFA6. The cited paper is an in-situ-hybridisation gene-mapping study that does not assay any catalytic activity of NDUFA6, which is a non-catalytic accessory subunit. Over-annotation; complex-level activity is captured via contributes_to_molecular_function in core_functions. Reason: PMID:9345899 screened cosmid and P1 libraries and used in situ hybridisation to place NDUFA6 at 21q22; it is a gene-mapping paper with no enzymology whatever, so it cannot support an `enables` claim for the holoenzyme's catalytic activity. The over-annotation is the same one carried by the NAS row above, and the same replacement applies. Proposed replacements: structural molecule activity Supporting Evidence: file:human/NDUFA6/NDUFA6-uniprot.txt chain NADH dehydrogenase (Complex I), that is believed to be not PMID:9345899 situ hybridisation studies we determined the following chromosome locations:

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