NDUFAF6

Gene Description

NDUFAF6 (C8orf38) is a nuclear-encoded mitochondrial assembly factor for respiratory chain complex I (NADH:ubiquinone oxidoreductase). The functional isoform (isoform 1) carries an N-terminal mitochondrial transit peptide and is imported into mitochondria, where it localizes peripherally on the matrix face of the inner membrane. It acts at early stages of complex I assembly and is specifically required for biogenesis of the mitochondrially encoded ND1 (MT-ND1) subunit, participating in formation/stabilization of the ND1-containing assembly intermediate; loss of NDUFAF6 blocks maturation of late-stage assembly intermediates and leads to a profound decrease in steady-state complex I. Structurally the protein retains an isoprenoid/squalene-phytoene-synthase-like (terpenoid synthase) fold, and although named a "putative phytoene synthase" no catalytic activity has been demonstrated; it is not a structural subunit of the holoenzyme. A shorter splice isoform (isoform 2) lacks the transit peptide and is cytoplasmic/nuclear. Biallelic NDUFAF6 variants cause mitochondrial complex I deficiency nuclear type 17 (including Leigh syndrome and bilateral striatal necrosis) and, via a non-coding intronic variant, the Acadian variant of Fanconi renotubular syndrome (FRTS5).

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference that NDUFAF6 is active in the mitochondrion. Consistent with the experimentally established mitochondrial inner-membrane localization of the functional isoform 1. Correct but general; the more specific inner-membrane term is the informative location for the core assembly-factor function. Supporting Evidence: file:human/NDUFAF6/NDUFAF6-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Mitochondrion inner membrane.
GO:0032981 mitochondrial respiratory chain complex I assembly	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference of the core biological process. Fully consistent with the direct experimental evidence (IMP, PMID:22019594) that NDUFAF6/C8orf38 is required for complex I assembly. This is the central, well-supported function of the gene. Supporting Evidence: file:human/NDUFAF6/NDUFAF6-uniprot.txt Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic annotation derived from the UniProt subcellular-location vocabulary. This reflects isoform 2, which lacks the mitochondrial transit peptide and localizes to cytoplasm/nucleus. It is not the compartment in which the complex I assembly function occurs, so it is retained as a genuine but non-core localization of a non-mitochondrial isoform. Supporting Evidence: file:human/NDUFAF6/NDUFAF6-uniprot.txt SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm. Nucleus.
GO:0005737 cytoplasm	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic (ARBA/SubCell) annotation. As with the nucleus annotation, this reflects the cytoplasmic isoform 2 rather than the mitochondrial isoform 1 that performs complex I assembly. Retained as a non-core, isoform-specific localization. Supporting Evidence: file:human/NDUFAF6/NDUFAF6-uniprot.txt SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm. Nucleus.
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: Electronic annotation from the UniProt subcellular-location vocabulary, matching the curated location of functional isoform 1 (peripherally on the matrix face of the inner membrane) and the direct experimental evidence in PMID:22019594. Accurate and represents the site of the core function. Supporting Evidence: file:human/NDUFAF6/NDUFAF6-uniprot.txt Note=Peripherally localized on the matrix face of the mitochondrial
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput proteomic detection of NDUFAF6 as part of the MitoCoP high-confidence human mitochondrial proteome. Corroborates mitochondrial localization; correct but non-specific relative to the curated inner-membrane term. Supporting Evidence: PMID:34800366 high-confidence mitochondrial proteome MitoCoP
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-6799179	ACCEPT	Summary: Reactome traceable-author annotation placing NDUFAF6 at the mitochondrial inner membrane within the Complex I biogenesis pathway. Consistent with the experimentally supported location; one of several redundant Reactome-derived inner-membrane annotations.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-6799191	ACCEPT	Summary: Reactome TAS annotation from the Complex I biogenesis pathway; the reaction involves the MT-ND1:NDUFAF5:NDUFAF6 subcomplex, directly reflecting the ND1-related assembly role of NDUFAF6 at the inner membrane. Accurate; redundant with the other inner-membrane annotations.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-6799196	ACCEPT	Summary: Reactome TAS annotation (Complex I biogenesis pathway) supporting inner-membrane localization. Accurate but redundant with the IDA and other Reactome inner-membrane annotations.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-6799197	ACCEPT	Summary: Reactome TAS annotation (Complex I biogenesis pathway) supporting inner-membrane localization. Accurate but redundant with the other inner-membrane annotations.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-6799202	ACCEPT	Summary: Reactome TAS annotation (Complex I biogenesis pathway) supporting inner-membrane localization. Accurate but redundant with the other inner-membrane annotations.
GO:0005743 mitochondrial inner membrane	IDA PMID:22019594 Mutations in the gene encoding C8orf38 block complex I assem...	ACCEPT	Summary: Direct experimental evidence for mitochondrial inner-membrane localization of NDUFAF6 (functional isoform 1), peripherally on the matrix face. This is the site of the core complex I assembly function and is the strongest location annotation for the gene. Supporting Evidence: file:human/NDUFAF6/NDUFAF6-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Mitochondrion inner membrane.
GO:0032981 mitochondrial respiratory chain complex I assembly	IMP PMID:22019594 Mutations in the gene encoding C8orf38 block complex I assem...	ACCEPT	Summary: Direct experimental (IMP) evidence for the core function. Patient fibroblasts carrying a C8orf38/NDUFAF6 mutation show almost undetectable steady-state complex I and defective biogenesis of the mtDNA-encoded ND1 subunit; complementation with wild-type C8orf38 restores both ND1 and complex I. This establishes NDUFAF6 as an early-stage complex I assembly factor required for ND1 biogenesis, and is the primary, best-supported annotation for the gene. Supporting Evidence: PMID:22019594 almost undetectable levels of steady-state complex I and defective biogenesis of the mtDNA-encoded subunit ND1

Gene Description

Existing Annotations Review

Core Functions

Mitochondrial complex I assembly factor that acts at early stages of complex I biogenesis and is specifically required for production/integration of the mitochondrially encoded ND1 (MT-ND1) subunit into the assembly intermediate.

References

📚 Additional Documentation

Notes

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