NDUFA12

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0045271 respiratory chain complex I	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically-inferred membership of NDUFA12 in respiratory chain Complex I. Correct and well supported by direct experimental structural/biochemical data (below); retained as background support for the core structural fact. Reason: The PAINT node assertion places Complex I membership on a clade that clearly includes human NDUFA12, and the same claim is independently established for this very protein by immunopurification/MS (PMID:12611891), CRISPR knockout proteomics (PMID:27626371) and cryo-EM subunit assignment (PMID:28844695). There is no human-specific evidence of loss or divergence that would argue against the node placement, so the inherited annotation is accepted rather than merely tolerated. Supporting Evidence: file:human/NDUFA12/NDUFA12-uniprot.txt Accessory subunit of the mitochondrial membrane respiratory
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic assignment of inner-membrane localization. Consistent with UniProt (mitochondrion inner membrane; peripheral membrane protein; matrix side) and with the ComplexPortal IDA below. Correct but redundant with the experimental annotation. Reason: Kept because it is correct, but marked non-core because the identical claim is carried by an experimental IDA annotation (PMID:28844695) that is the annotation of record for this localization. The electronic assertion adds no information beyond it. Supporting Evidence: file:human/NDUFA12/NDUFA12-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane
GO:0016020 membrane	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Generic 'membrane' term from InterPro2GO. Uninformative given the specific, experimentally supported localization to the mitochondrial inner membrane (matrix side); over-general and superseded. Reason: The InterPro2GO mapping fires on a domain signature shared across membrane- associated proteins and can only license the most general parent term. Because UniProt and the cryo-EM structure localize NDUFA12 precisely to the matrix face of the mitochondrial inner membrane, GO:0016020 is a strictly less informative ancestor of GO:0005743 that the gene already carries; it is flagged as over-general rather than removed, since it is not factually wrong. Supporting Evidence: file:human/NDUFA12/NDUFA12-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane file:human/NDUFA12/NDUFA12-uniprot.txt Matrix side
GO:0045271 respiratory chain complex I	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic assertion of Complex I membership; correct but redundant with the IDA/IMP/IPI experimental annotations that establish this as the core structural fact. Reason: Correct, but the same term is asserted for this protein by three independent experimental annotations (IDA, IPI, IMP). The electronic call is therefore retained as corroboration and demoted to non-core so that the experimental evidence remains the annotation of record.
GO:1902600 proton transmembrane transport	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	Summary: Inferred by logical inference from the GO:0008137 'NADH dehydrogenase (ubiquinone) activity' MF annotation. That MF annotation is itself an over-annotation for this non-catalytic accessory subunit (see below), and NDUFA12 does not itself translocate protons. Proton pumping is a complex-level activity carried out by the membrane-arm core (ND) subunits, not by NDUFA12. Reason: This is a purely logical (inter-ontology) inference whose premise is the GO:0008137 NAS annotation flagged below as an over-annotation; an inference is no stronger than its premise. Independently, the entity that performs proton translocation is the antiporter-like membrane-arm core (ND2/ND4/ND5), whereas NDUFA12 is a peripheral matrix-arm subunit that UniProt states is not involved in catalysis, so it does none of the work of this process. Supporting Evidence: file:human/NDUFA12/NDUFA12-uniprot.txt involved in catalysis. file:human/NDUFA12/NDUFA12-uniprot.txt Matrix side
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), with partner TMED8 (Q6PL24). The term is uninformative and the Y2H partner is not among the physiologically relevant Complex I contacts of NDUFA12; kept per policy but flagged as over-annotated rather than a meaningful molecular function. Reason: 'Protein binding' conveys no functional information, and the interaction is a systematic all-by-all yeast two-hybrid hit rather than a directed assay of a physiological partner; the authors themselves note that the cellular function of most individual PPIs in the map remains to be elucidated. NDUFA12's biologically meaningful contacts are its neighbouring Complex I subunits in the matrix arm, which this screen does not report. Per curation policy a bare protein-binding IPI is never removed, so it is flagged as over-annotated instead. Supporting Evidence: PMID:32296183 the cellular function of most individual PPIs remains to be elucidated
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 same high-throughput binary interactome screen (HuRI), with partner MYO15B (Q96JP2). An unconventional myosin-family protein is not a plausible physiological partner for a matrix-arm Complex I subunit; kept per policy but flagged as over-annotated rather than a meaningful molecular function. Reason: 'Protein binding' conveys no functional information, and the interaction is a systematic all-by-all yeast two-hybrid hit rather than a directed assay of a physiological partner; the authors themselves note that the cellular function of most individual PPIs in the map remains to be elucidated. NDUFA12's biologically meaningful contacts are its neighbouring Complex I subunits in the matrix arm, which this screen does not report. Per curation policy a bare protein-binding IPI is never removed, so it is flagged as over-annotated instead. Supporting Evidence: PMID:32296183 the cellular function of most individual PPIs remains to be elucidated
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 same high-throughput binary interactome screen (HuRI), with partner SYT4 (Q9H2B2). A synaptic-vesicle synaptotagmin is not a plausible physiological partner for a matrix-arm Complex I subunit; kept per policy but flagged as over-annotated rather than a meaningful molecular function. Reason: 'Protein binding' conveys no functional information, and the interaction is a systematic all-by-all yeast two-hybrid hit rather than a directed assay of a physiological partner; the authors themselves note that the cellular function of most individual PPIs in the map remains to be elucidated. NDUFA12's biologically meaningful contacts are its neighbouring Complex I subunits in the matrix arm, which this screen does not report. Per curation policy a bare protein-binding IPI is never removed, so it is flagged as over-annotated instead. Supporting Evidence: PMID:32296183 the cellular function of most individual PPIs remains to be elucidated
GO:0005739 mitochondrion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronic transfer of mitochondrial localization from mouse ortholog. Correct but coarser than the experimentally supported inner-membrane / Complex I localization. Reason: The Compara orthology call is sound - NDUFA12 orthologs are mitochondrial across vertebrates - but GO:0005739 is an ancestor of the inner-membrane term that this protein already carries experimentally, so it is retained only as consistent background.
GO:0005743 mitochondrial inner membrane	IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ...	ACCEPT	Summary: Direct assay (cryo-EM of the human respiratory megacomplex, ComplexPortal curation) placing NDUFA12 in the mitochondrial inner membrane as part of Complex I. This is the core, experimentally grounded localization (matrix-side peripheral inner membrane). Reason: Cryo-EM of the intact human megacomplex assigned each Complex I subunit to a position in the structure, which localizes NDUFA12 to the inner membrane by direct observation rather than by inference. This agrees with UniProt's peripheral inner-membrane, matrix-side assignment, so it is accepted as the core localization. Supporting Evidence: PMID:28844695 The structure not only reveals the precise assignment of individual subunits of file:human/NDUFA12/NDUFA12-uniprot.txt Matrix side
GO:0009060 aerobic respiration	NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-...	KEEP AS NON CORE	Summary: Complex-level process attributed by ComplexPortal from a review of OXPHOS assembly. Aerobic respiration is a role of Complex I as a whole; NDUFA12 participates only structurally. True but not a distinct NDUFA12 molecular contribution, so retained as non-core. Reason: The cited source is a review asserting that supernumerary subunits matter for assembly, regulation and stability; it does not show that NDUFA12 performs any step of aerobic respiration. The annotation is true of the holoenzyme NDUFA12 belongs to, so it is kept as complex-level context rather than as a NDUFA12-specific process. 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-...	KEEP AS NON CORE	Summary: Complex-level (OXPHOS) contribution attributed by ComplexPortal. NDUFA12 as a structural subunit contributes to a functional Complex I that helps generate the proton-motive force, but does not itself drive ATP synthesis; retained as non-core context. Reason: ATP synthesis driven by the proton-motive force is performed by Complex V; Complex I contributes upstream by pumping protons, and NDUFA12 contributes to Complex I only structurally. The claim is two steps removed from anything NDUFA12 does itself, so it is retained as pathway context and excluded from the core functions. 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: Physical-interaction (cryo-EM, ComplexPortal) evidence assigning NDUFA12 to Complex I. Directly supports the core structural fact that NDUFA12 is a subunit of the mature holoenzyme. Reason: The megacomplex structure resolves 140 subunits and assigns them individually, which is direct physical evidence that NDUFA12 is a constituent of the assembled Complex I 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	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Immunofluorescence (HPA) localization to mitochondrion. Correct but coarser than the inner-membrane / Complex I localization; retained as supporting, non-core. Reason: Immunofluorescence resolves organelle but not submitochondrial compartment, so this assay can only support the parent term. It corroborates the more specific inner-membrane annotations without superseding them. No primary publication is attached to this HPA-derived annotation, so no literature quote is offered. Supporting Evidence: file:human/NDUFA12/NDUFA12-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	KEEP AS NON CORE	Summary: High-throughput mitochondrial-proteome localization to mitochondrion. Consistent but coarse; redundant with the more specific inner-membrane annotations. Reason: MitoCoP is a high-confidence, quantitatively filtered mitochondrial proteome, so inclusion of NDUFA12 is trustworthy evidence of mitochondrial residence, but a whole-organelle proteomic assay cannot distinguish inner membrane from matrix. Retained as corroboration at a coarser granularity than the IDA annotations. 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 identification of NDUFA12 (the differentiation-linked 13 kDa protein, DAP13) as a subunit of immunopurified human Complex I by mass spectrometry. Core, foundational experimental evidence for Complex I membership. Reason: One-step immunocapture of the intact complex followed by MALDI-TOF peptide mass fingerprinting and LC-MS/MS identified 42 polypeptides, among them the differentiation-associated protein that is NDUFA12/DAP13. Co-purification with the immunoisolated holoenzyme is direct evidence of subunit status, and the authors note the concordance with independently purified bovine Complex I. Supporting Evidence: PMID:12611891 differentiation linked processes PMID:12611891 homologues of 42 polypeptides detected so far in the more extensively studied
GO:0045271 respiratory chain complex I	IMP PMID:24746669 Cyclin B1/Cdk1 coordinates mitochondrial respiration for cel...	ACCEPT	Summary: Mutation/phenotype evidence associating NDUFA12 with Complex I. Complex I membership itself is robustly established; accepted as consistent with the core structural fact. Reason: The cached record is abstract-only and names Complex I subunits generically, but the curator worked from the full text, and the conclusion drawn - that NDUFA12 is part of Complex I - is independently established by structural and proteomic evidence. There is no ground to second-guess the annotation, so it is accepted. Supporting Evidence: PMID:24746669 mitochondrial proteins, including the complex I (CI) subunits in the respiratory
GO:0045271 respiratory chain complex I	IDA PMID:27626371 Accessory subunits are integral for assembly and function of...	ACCEPT	Summary: Direct (CRISPR knockout + quantitative proteomics) evidence that NDUFA12 is an accessory subunit of human Complex I. Establishes it as an integral, non-catalytic component of the holoenzyme (its slot can be substituted by the NDUFAF2 paralog in knockouts). Core structural annotation. Reason: Gene-edited knockout lines were generated for every accessory subunit and profiled by quantitative proteomics, which both confirms NDUFA12 as a constituent of the complex and places it within a specific structural module. UniProt's derived MISCELLANEOUS note from this work - that assembly survives NDUFA12 loss because NDUFAF2 substitutes - presupposes that NDUFA12 normally occupies that slot. Accepted as core. Supporting Evidence: PMID:27626371 Accessory subunits are integral for assembly and function of human PMID:27626371 Here we use gene editing to generate human knockout file:human/NDUFA12/NDUFA12-uniprot.txt believed not to be
GO:0042775 mitochondrial ATP synthesis coupled electron transport	IMP PMID:24746669 Cyclin B1/Cdk1 coordinates mitochondrial respiration for cel...	KEEP AS NON CORE	Summary: Experimental (IMP) annotation from a study of cyclin B1/Cdk1 phosphorylation of Complex I subunits enhancing CI activity for G2/M progression. This is a complex-level electron-transport role and a cell-cycle regulatory context rather than NDUFA12's core evolved molecular function; retained (not removed, being experimental) as non-core. Reason: The phenotype reported is loss of Complex I activity when phosphorylation of a CI subunit is prevented, which demonstrates that the subunit is required for normal complex-level electron transport under a cell-cycle stimulus. That is genuine experimental evidence and is not overruled here, but the process is carried out by the core redox subunits of the complex; NDUFA12's contribution is structural. Kept as non-core context. Supporting Evidence: PMID:24746669 Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-163217	KEEP AS NON CORE	Summary: Reactome traceable-author localization to mitochondrial inner membrane. Correct and consistent with the experimental inner-membrane annotation; redundant. Reason: The Reactome reaction places the whole Complex I holoenzyme, and hence each of its subunits, in the inner membrane. That is correct but is an assertion about the complex rather than an independent observation of NDUFA12, and the same localization is carried by an IDA annotation. Kept as consistent, non-core corroboration. Reactome entries carry 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-6799179	KEEP AS NON CORE	Summary: Reactome traceable-author localization to mitochondrial inner membrane (Complex I biogenesis pathway). Consistent; redundant with the experimental annotation. Reason: This Reactome step explicitly names NDUFA12 among the peripheral-arm (flavoprotein subcomplex) subunits that join the 815 kDa intermediate, which is an accurate placement within the assembling holoenzyme. The peripheral arm protrudes into the matrix rather than sitting within the bilayer, so the inner-membrane localization is a property of the complex NDUFA12 joins rather than of the subunit itself. It duplicates the experimental inner-membrane localization, so it is retained as non-core. 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-6799196	KEEP AS NON CORE	Summary: Reactome traceable-author localization to mitochondrial inner membrane. Consistent and correct; redundant with the experimental inner-membrane annotation. Reason: Derived from the same Complex I biogenesis pathway as the other Reactome localizations and asserting the same compartment. Correct but not independent evidence, so non-core. 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-6800870	KEEP AS NON CORE	Summary: Reactome traceable-author localization to mitochondrial inner membrane. Consistent and correct; redundant with the experimental inner-membrane annotation. Reason: A further step of the same Reactome Complex I biogenesis pathway, asserting the same compartment for the assembling complex. Retained as consistent background rather than as the annotation of record. Supporting Evidence: Reactome:R-HSA-6800870 NDUF subunits bind to form the FP subcomplex
GO:0008137 NADH dehydrogenase (ubiquinone) activity	NAS PMID:10830904 Characterization of the human complex I NDUFB7 and 17.2-kDa ...	MARK AS OVER ANNOTATED	Summary: 'Enables NADH dehydrogenase (ubiquinone) activity' is an over-annotation for NDUFA12: UniProt states it is 'believed not to be involved in catalysis', and it is a supernumerary structural subunit, not a redox catalytic subunit. This complex-level activity is carried out by the core (NDUFS/NDUFV/ND) subunits. NDUFA12 should be represented as contributing_to this activity (via structural molecule activity), not as enabling it directly. The NAS derives from the enzyme name in the original cDNA paper, not from a demonstrated catalytic activity of this subunit. Reason: The cited paper is a cDNA characterization and mutation screen of the hydrophobic fraction subunits; it reports no enzymological assay of the 17.2-kDa protein, so the MF assignment reflects the name of the parent enzyme rather than a measured activity. The redox chemistry requires FMN and the Fe-S cluster chain carried by the NDUFV/NDUFS core subunits, none of which NDUFA12 possesses. The correct representation is contributes_to GO:0008137 with a structural molecule activity MF, which is how core_functions records it. Proposed replacements: structural molecule activity Supporting Evidence: file:human/NDUFA12/NDUFA12-uniprot.txt involved in catalysis. PMID:10830904 17.2-kDa cDNA sequences of the hydrophobic (HP) fraction of the complex.

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