NDUFAF8 (formerly C17orf89) is a small (74 aa) soluble mitochondrial protein that acts as an assembly factor for respiratory chain Complex I (NADH:ubiquinone oxidoreductase). It is not a structural subunit of the mature holoenzyme and has no known catalytic activity. NDUFAF8 carries a twin CX9C / CHCH domain stabilized by two intramolecular disulfide bonds, the hallmark of substrates of the mitochondrial MIA40/CHCHD4 disulfide-relay import system; it reaches the mitochondrial matrix via a two-step import pathway in which a weak targeting sequence drives slow TIM23-dependent matrix import while allowing en-route oxidation by the intermembrane-space disulfide relay. In the matrix it binds and stabilizes the early Complex I assembly factor NDUFAF5, which is required for maturation of the Q module during early Complex I (NADH:ubiquinone oxidoreductase) biogenesis. Loss of NDUFAF8 destabilizes NDUFAF5 and stalls Q-module assembly, producing an isolated Complex I deficiency; bi-allelic loss-of-function variants cause a mitochondrial Complex I deficiency (Leigh syndrome, MC1DN34).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) mitochondrial localization. NDUFAF8 is a mitochondrial assembly factor, so mitochondrial localization is correct, but this is subsumed by the more specific and directly-supported mitochondrial matrix localization (GO:0005759, IDA). Kept as non-core. Supporting Evidence: file:human/NDUFAF8/NDUFAF8-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0032981 mitochondrial respiratory chain complex I assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) support for the core biological process. NDUFAF8 is a validated Complex I assembly factor; this agrees with the experimental IMP (PMID:27499296). Represents the core function of the gene. Supporting Evidence: PMID:27499296 we validated C17orf89 as a complex I (CI) assembly factor |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (IEA) mitochondrial localization. Consistent with the experimental data; subsumed by the more specific mitochondrial matrix localization. Kept as non-core. Supporting Evidence: file:human/NDUFAF8/NDUFAF8-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0032981 mitochondrial respiratory chain complex I assembly | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO (IEA) mapping of the NDUFAF8 family signature (IPR034595) to the Complex I assembly process. This correctly captures the core function and is corroborated by experimental IMP evidence. Supporting Evidence: PMID:27499296 we validated C17orf89 as a complex I (CI) assembly factor |
| GO:0005515 protein binding | IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat... | MARK AS OVER ANNOTATED | Summary: IPI interaction with UniProtKB:Q5TEU4 (NDUFAF5). This is the biologically meaningful, focused interaction (IntAct NbExp=11) that underlies NDUFAF8 function: NDUFAF8 binds and is required to stabilize NDUFAF5. The bare "protein binding" term is uninformative, but the NDUFAF5 interaction is the mechanistic basis of the core assembly-factor role. Per policy an IPI protein-binding annotation is retained rather than removed; flagged as over-annotated because the specific partner/role (NDUFAF5 stabilization) is captured in core_functions. Supporting Evidence: file:human/NDUFAF8/NDUFAF8-uniprot.txt Required to stabilize NDUFAF5 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: IPI interaction with UniProtKB:Q5TEU4 (NDUFAF5) from the BioPlex (Huttlin 2017) large-scale AP-MS interactome. Corroborates the NDUFAF5 interaction but the bare "protein binding" term is uninformative and this is high-throughput. Retained (IPI) but marked over-annotated. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IPI interaction with UniProtKB:Q5TEU4 (NDUFAF5) from the BioPlex 3.0 (Huttlin 2021) proteome-scale AP-MS interactome. Corroborates the NDUFAF5 interaction; bare "protein binding" term is uninformative and this is high-throughput. Retained (IPI) but marked over-annotated. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: IDA mitochondrial localization from curated immunofluorescence (HPA). Consistent with the experimental data; subsumed by the more specific mitochondrial matrix localization. Kept as non-core. Supporting Evidence: file:human/NDUFAF8/NDUFAF8-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput (HTP) mitochondrial-proteome detection supports mitochondrial localization. Consistent with experimental data; subsumed by the more specific matrix localization. Kept as non-core. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in |
| GO:0005759 mitochondrial matrix | IDA PMID:37159021 A two-step mitochondrial import pathway couples the disulfid... | ACCEPT | Summary: IDA mitochondrial matrix localization. This is the accurate, most specific location: NDUFAF8 transits the intermembrane space (where its disulfide bonds are formed) but its functional destination is the matrix, where it stabilizes NDUFAF5. Represents the core cellular location of NDUFAF8 function. Supporting Evidence: PMID:37159021 A weak targeting sequence drives TIM23-dependent NDUFAF8 matrix import |
| GO:0005739 mitochondrion | IDA PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat... | KEEP AS NON CORE | Summary: IDA mitochondrial localization from Floyd et al. 2016, the experimental reference underlying the UniProt subcellular-location statement. Correct but subsumed by the more specific matrix localization (GO:0005759). Kept as non-core. Supporting Evidence: file:human/NDUFAF8/NDUFAF8-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:27499296} |
| GO:0032981 mitochondrial respiratory chain complex I assembly | IMP PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat... | ACCEPT | Summary: IMP evidence from Floyd et al. 2016: disruption of C17orf89 (NDUFAF8) markedly reduced Complex I activity, validating it as a Complex I assembly factor. This is the core, experimentally-established biological process of the gene. Supporting Evidence: PMID:27499296 Disruption of C17orf89 markedly reduced CI activity |
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