NDUFA8 (also known as Complex I-19kD, CI-PGIV) is a nuclear-encoded accessory (supernumerary) subunit of mitochondrial respiratory chain Complex I (NADH:ubiquinone oxidoreductase), the first and largest enzyme of the oxidative phosphorylation system. It is a non-catalytic structural subunit: catalysis (electron transfer from NADH to ubiquinone, coupled to proton translocation) is performed by the 14 conserved core subunits, while NDUFA8 and the other accessory subunits contribute to assembly, stability, and structural integrity of the holoenzyme. NDUFA8 is a twin CX9C protein containing four C-X9-C motifs that fold into a helix-coil-helix (CHCH) domain stabilized by two pairs of intramolecular disulfide bonds; it is imported and oxidatively folded via the MIA40/CHCHD4 disulfide-relay pathway of the mitochondrial intermembrane space. The mature protein is a peripheral inner-membrane protein located at the intermembrane-space surface of the membrane arm of Complex I, where it (together with NDUFB7) is thought to help stabilize the membrane domain. Biallelic loss-of-function variants in NDUFA8 cause autosomal-recessive mitochondrial complex I deficiency nuclear type 37, with reduced Complex I assembly and activity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0045271 respiratory chain complex I | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that NDUFA8 is part_of respiratory chain complex I. This is correct and well supported: NDUFA8 is a bona fide accessory subunit of Complex I, confirmed by immunopurification/MS and cryo-EM structures. Core cellular-component annotation. Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt Accessory subunit of the mitochondrial membrane respiratory |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (IEA) mitochondrion localization. Correct but the least specific of the localization annotations; the inner-membrane / respiratory-chain-complex-I / intermembrane-space terms are more informative. Keep as non-core. Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (IEA) mitochondrial inner membrane localization, duplicating the experimentally supported inner-membrane annotations below. NDUFA8 is a peripheral inner-membrane protein (IMS-facing) as part of the Complex I membrane arm. Accurate; kept as non-core given the more specific respiratory-chain-complex-I membership captures the functional location. Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt Mitochondrion inner membrane |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic (IEA, SubCell mapping) intermembrane-space localization. Consistent with the experimental finding that NDUFA8 sits at the IMS surface of Complex I and with its MIA40-relay CX9C import. Correct; duplicates the IDA IMS annotation below. Non-core (a more granular facet of the inner-membrane location). Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt Mitochondrion intermembrane space |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic (InterPro2GO) involvement in mitochondrial electron transport, NADH to ubiquinone. This is the correct pathway-level process for a Complex I subunit: NDUFA8 does not itself transfer electrons, but as an integral structural subunit it is required for the holoenzyme that carries out this process. Retained as a core biological process (captured in core_functions). Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt Accessory subunit of the mitochondrial membrane respiratory |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Electronic term inferred logically from GO:0008137 (NADH dehydrogenase activity). Proton translocation is a property of the Complex I holoenzyme, driven by the membrane-arm antiporter-like core subunits; NDUFA8 is a non-catalytic accessory subunit and does not itself transport protons. This is a complex/pathway-level process, not the molecular activity of NDUFA8, so it is an over-annotation for this subunit. Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt that is believed not to be |
| GO:0005515 protein binding | IPI PMID:21310150 NDUFB7 and NDUFA8 are located at the intermembrane surface o... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) with NDUFS3 (O75489). NDUFA8 and NDUFS3 are both Complex I subunits and are recorded as interacting in UniProt (NbExp=5). The interaction is real but "protein binding" is uninformative and merely reflects co-membership in Complex I; the specific relationship is better captured by the part_of respiratory chain complex I annotation. Marked as over-annotated per the guideline to avoid bare protein binding as a molecular function. Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt Complex I is composed of 45 different subunits |
| GO:0005515 protein binding | IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) with NDUFS3 (O75489) from a mitochondrial affinity- enrichment MS interactome study. Real physical interaction between two Complex I subunits, but "protein binding" conveys no specific molecular function and is redundant with Complex I membership. Over-annotated. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) with DMWD (G5E9A7) and SPRED1 (Q7Z699) from a large-scale neurodegenerative-disease yeast-two-hybrid interactome. These are high-throughput binary interaction hits, not functional partners informing NDUFA8's molecular activity, and "protein binding" is uninformative. Over-annotated. |
| GO:0045271 respiratory chain complex I | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (IEA) part_of respiratory chain complex I, duplicating the IBA and the experimental (IDA/IPI) Complex I membership annotations. Correct core localization; retained as core via the experimental annotations, this electronic duplicate kept as non-core. Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt Accessory subunit of the mitochondrial membrane respiratory |
| GO:0005743 mitochondrial inner membrane | IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | KEEP AS NON CORE | Summary: IDA inner-membrane localization from the cryo-EM megacomplex I2III2IV2 structure (ComplexPortal), which resolves NDUFA8 within the Complex I membrane arm at the inner membrane. Accurate and experimentally grounded. The functional location is more precisely captured by respiratory chain complex I membership; kept as non-core. |
| GO:0009060 aerobic respiration | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | KEEP AS NON CORE | Summary: NAS (ComplexPortal) involvement in aerobic respiration. This is a high-level process attributable to the whole OXPHOS system rather than the specific activity of NDUFA8; NDUFA8's contribution is via being a Complex I subunit. Correct at the pathway level but too general to be a core function of this subunit; kept as non-core. |
| GO:0042776 proton motive force-driven mitochondrial ATP synthesis | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | MARK AS OVER ANNOTATED | Summary: NAS (ComplexPortal) involvement in proton-motive-force-driven ATP synthesis. ATP synthesis is carried out by Complex V (ATP synthase); Complex I contributes only by helping generate the proton gradient, and NDUFA8 is a non-catalytic subunit of Complex I. This is a downstream, complex/pathway-level process incorrectly ascribed to the individual subunit's function; over-annotation for NDUFA8. Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt that is believed not to be |
| GO:0045271 respiratory chain complex I | IPI PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: Complex I membership (IPI/part_of) supported by the cryo-EM megacomplex structure resolving NDUFA8 within Complex I. Correct core cellular-component annotation. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: IDA mitochondrion localization from immunofluorescence (HPA). Correct but the least specific localization; superseded by the inner-membrane / Complex I annotations. Non-core. Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt Mitochondrion inner membrane |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput (HTP) mitochondrion localization from a high-confidence human mitochondrial proteome study. Correct but non-specific; consistent with NDUFA8 being a mitochondrial Complex I subunit. Non-core. |
| GO:0045271 respiratory chain complex I | IDA PMID:12611891 The subunit composition of the human NADH dehydrogenase obta... | ACCEPT | Summary: IDA Complex I membership from one-step immunopurification of human Complex I followed by MS identification of its subunits, which detected NDUFA8 among the Complex I polypeptides. Strong experimental support for the core cellular-component annotation. |
| GO:0045271 respiratory chain complex I | IDA PMID:27626371 Accessory subunits are integral for assembly and function of... | ACCEPT | Summary: IDA Complex I membership from the CRISPR knockout / quantitative-proteomics study of human Complex I accessory subunits, which places NDUFA8 as an integral subunit whose loss destabilizes its structural module. Strong support for the core cellular-component annotation. Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt Accessory subunit of the mitochondrial membrane respiratory |
| GO:0045271 respiratory chain complex I | NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox... | KEEP AS NON CORE | Summary: NAS Complex I membership from the cDNA characterization of nuclear-encoded Complex I subunits. Correct; redundant with the experimentally supported Complex I membership annotations. Retained as core via the IDA annotations; this NAS duplicate kept as non-core. |
| GO:0005743 mitochondrial inner membrane | EXP PMID:21310150 NDUFB7 and NDUFA8 are located at the intermembrane surface o... | KEEP AS NON CORE | Summary: Experimental (EXP) inner-membrane localization from the study that placed NDUFB7 and NDUFA8 at the intermembrane-space surface of Complex I in the inner membrane. NDUFA8 is a peripheral inner-membrane protein. Accurate; functional location is captured by Complex I membership, so kept as non-core. Supporting Evidence: PMID:21310150 NDUFB7 and NDUFA8 are located at the intermembrane surface of complex I |
| GO:0044877 protein-containing complex binding | IDA PMID:23209302 KIF14 negatively regulates Rap1a-Radil signaling during brea... | MARK AS OVER ANNOTATED | Summary: IDA "protein-containing complex binding" attributed to PMID:23209302. That paper ("KIF14 negatively regulates Rap1a-Radil signaling during breast cancer progression") is about KIF14/Radil/Rap1a signaling in breast cancer and does not concern NDUFA8 or mitochondrial Complex I (full text checked; no mention of NDUFA8), so the citation appears to point to the wrong paper (see reference_review). The concept is in any case uninformative for NDUFA8: it is trivially true that a Complex I subunit binds a protein-containing complex, and this is fully captured by the specific part_of respiratory chain complex I annotation. Marked as over-annotated rather than removed, per policy on experimental annotations. Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt Complex I is composed of 45 different subunits |
| GO:0005739 mitochondrion | IDA PMID:23676665 Protein import and oxidative folding in the mitochondrial in... | KEEP AS NON CORE | Summary: IDA mitochondrion localization from the study of MIA40/ALR-mediated oxidative protein import/folding in the mammalian intermembrane space; NDUFA8, a CX9C disulfide-relay substrate, is a mitochondrial protein. Correct but non-specific compared with the inner-membrane / Complex I annotations. Non-core. Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt Mitochondrion intermembrane space |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-163217 | KEEP AS NON CORE | Summary: TAS inner-membrane localization from Reactome (Complex I oxidises NADH to NAD+ reaction). Accurate location for a Complex I subunit; redundant with the experimental inner-membrane annotations. Non-core. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799178 | KEEP AS NON CORE | Summary: TAS inner-membrane localization from a Reactome Complex I biogenesis reaction. Correct location; redundant with experimental annotations. Non-core. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799179 | KEEP AS NON CORE | Summary: TAS inner-membrane localization from a Reactome Complex I assembly reaction. Correct location; redundant with experimental annotations. Non-core. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799191 | KEEP AS NON CORE | Summary: TAS inner-membrane localization from a Reactome Complex I assembly reaction. Correct location; redundant with experimental annotations. Non-core. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799196 | KEEP AS NON CORE | Summary: TAS inner-membrane localization from a Reactome Complex I assembly reaction. Correct location; redundant with experimental annotations. Non-core. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799197 | KEEP AS NON CORE | Summary: TAS inner-membrane localization from a Reactome Complex I assembly reaction. Correct location; redundant with experimental annotations. Non-core. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799202 | KEEP AS NON CORE | Summary: TAS inner-membrane localization from a Reactome Complex I assembly reaction. Correct location; redundant with experimental annotations. Non-core. |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:21310150 NDUFB7 and NDUFA8 are located at the intermembrane surface o... | ACCEPT | Summary: IDA intermembrane-space localization from the study demonstrating NDUFA8 (and NDUFB7) at the IMS surface of Complex I. This is the most informative single- subunit localization for NDUFA8 (it faces the IMS from the inner membrane) and is consistent with its MIA40-relay CX9C import. Accurate; captured in core_functions as a facet of its inner-membrane location. Supporting Evidence: PMID:21310150 NDUFB7 and NDUFA8 are located at the intermembrane surface of complex I file:human/NDUFA8/NDUFA8-uniprot.txt Mitochondrion intermembrane space |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox... | ACCEPT | Summary: NAS involvement in mitochondrial electron transport, NADH to ubiquinone. This is the appropriate pathway-level biological process for a Complex I subunit: NDUFA8 is required for the holoenzyme that performs this process, though it is not itself catalytic. Retained as a core biological process. Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt Accessory subunit of the mitochondrial membrane respiratory |
| 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 annotates NDUFA8 as directly enabling NADH dehydrogenase (ubiquinone) activity. That catalytic activity is carried out by the conserved core subunits (FMN/Fe-S-bearing subunits) of Complex I. UniProt explicitly states NDUFA8 is an accessory subunit believed not to be involved in catalysis. Assigning the catalytic MF directly to a non-catalytic accessory subunit is an over-annotation; the honest relationship is captured in core_functions via contributes_to_molecular_function (GO:0008137), with the subunit's own MF being structural molecule activity (GO:0005198). Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt involved in catalysis |
| GO:0008137 NADH dehydrogenase (ubiquinone) activity | TAS PMID:9860297 The nuclear-encoded human NADH:ubiquinone oxidoreductase NDU... | MARK AS OVER ANNOTATED | Summary: TAS annotation of NDUFA8 directly enabling NADH dehydrogenase (ubiquinone) activity, from the original cDNA-cloning paper. As above, catalysis is a property of the Complex I core subunits, not of the non-catalytic accessory subunit NDUFA8. Over-annotation at the subunit level; the contribution is represented via contributes_to_molecular_function (GO:0008137) in core_functions. Supporting Evidence: file:human/NDUFA8/NDUFA8-uniprot.txt involved in catalysis |
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