NDUFA12 (B17.2; also called the 13 kDa differentiation-associated protein, DAP13) is an accessory (supernumerary) subunit of mitochondrial respiratory Complex I (NADH:ubiquinone oxidoreductase), the first enzyme of the mitochondrial electron transport chain. It is a stable structural subunit of the mature holoenzyme, located in the peripheral (matrix) arm near the junction of the N- and Q-modules, and is a peripheral inner-membrane protein exposed to the matrix. NDUFA12 is non-catalytic: it does not itself carry out NADH oxidation, quinone reduction, or proton pumping, but contributes structurally to the assembly and stability of a fully functional Complex I that transfers electrons from NADH to ubiquinone and contributes to the proton-motive force used for ATP synthesis. It is distinct from its paralog NDUFAF2/NDUFA12L, which is a Complex I assembly factor rather than a mature-enzyme subunit; in NDUFA12-knockout cells the assembly factor NDUFAF2 can substitute in the complex. Biallelic loss-of-function variants in NDUFA12 cause mitochondrial complex I deficiency (nuclear type 23) and Leigh syndrome.
| 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. 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. 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the specific, experimentally supported localization to the mitochondrial inner membrane (matrix side); over-general and superseded. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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). Supporting Evidence: 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. Supporting Evidence: PMID:12611891 differentiation linked processes |
| 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. |
| 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. Supporting Evidence: 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. Proposed replacements: structural molecule activity Supporting Evidence: file:human/NDUFA12/NDUFA12-uniprot.txt involved in catalysis. |
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