NDUFA10 (O95299) — Gene Review Notes

Identity and overview

• Gene: NDUFA10 (HGNC:7684); UniProt O95299 (NDUAA_HUMAN).
• Product: "NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial"; aka Complex I-42kD / CI-42kD, "NADH-ubiquinone oxidoreductase 42 kDa subunit" [file:human/NDUFA10/NDUFA10-uniprot.txt "AltName: Full=Complex I-42kD"].
• Precursor with an N-terminal mitochondrial transit peptide (residues 1–35); mature chain 36–355 [file:human/NDUFA10/NDUFA10-uniprot.txt "TRANSIT 1..35"].

Core biology: accessory (supernumerary) subunit of Complex I membrane arm

• UniProt FUNCTION: "Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone." (ECO:0000269|PubMed:27626371) [file:human/NDUFA10/NDUFA10-uniprot.txt "believed not to be involved in catalysis"].
• SUBUNIT: "Complex I is composed of 45 different subunits. This a component of the hydrophobic protein fraction." (ECO:0000269|PubMed:12611891, PubMed:27626371) [file:human/NDUFA10/NDUFA10-uniprot.txt "component of the hydrophobic protein"]. The HP fraction is the membrane arm.
• Human complex I = 14 conserved core subunits (catalytic) + 31 accessory/supernumerary subunits; the core subunits are essential for enzymatic function and the accessory subunits have less clear individual roles PMID:27626371.
• Stroud et al. knocked out each accessory subunit; 25 are strictly required to assemble a functional complex, and loss of a subunit destabilizes other subunits in the same structural module PMID:27626371. This establishes accessory subunits (including NDUFA10) as structural/assembly components rather than catalytic.

dNK (deoxyribonucleoside kinase) fold — pseudoenzyme, no assigned catalytic activity

• Structural/domain annotations place NDUFA10 in a deoxyribonucleoside kinase (dNK) / P-loop NTPase fold: InterPro IPR050566 (Deoxyribonucleoside_kinase), IPR031314 (DNK_dom), Pfam PF01712 (dNK), CDD cd02030 (NDUO42), PANTHER PTHR10513 (DEOXYNUCLEOSIDE KINASE), Gene3D 3.40.50.300 (P-loop NTPase) [file:human/NDUFA10/NDUFA10-uniprot.txt "InterPro; IPR050566; Deoxyribonucleoside_kinase"].
• However, UniProt assigns NO catalytic activity (no CATALYTIC ACTIVITY / EC line) and explicitly states the subunit is "believed not to be involved in catalysis." The dNK fold here is a structural scaffold; NDUFA10 is a pseudokinase / pseudoenzyme in the complex I context. The FAD cofactor note ("Binds 1 FAD per subunit") is a family/structural feature, not evidence of a nucleoside-kinase catalytic function.
• Consequence for GO: a nucleoside/nucleotide kinase molecular function should NOT be assigned from the fold — that would be a classic fold-based pseudoenzyme over-annotation. The honest MF for a structural subunit is GO:0005198 structural molecule activity, contributing to the complex-level catalysis (GO:0008137) via contributes_to, not enables.

Localization

• Mature protein resides in the mitochondrial inner membrane as part of the complex I membrane arm; ComplexPortal annotates it to GO:0005743 (mitochondrial inner membrane) IDA PMID:28844695.
• UniProt SUBCELLULAR LOCATION line reads "Mitochondrion matrix" (ECO:0000305|PubMed:12611891) — this is a topological inference for a matrix-facing accessory subunit and is the source of the GO:0005759 IEA (UniProtKB-SubCell) annotation. The membrane-arm inner-membrane localization (GO:0005743) is better supported by structural/ComplexPortal evidence.
• NDUFA10 is a high-confidence mitochondrial proteome member; MitoCoP defines ">1,100 proteins" PMID:34800366 (source of the GO:0005739 mitochondrion HTP annotation).

Complex I structure / assembly context

• Identified as one of the ~42 human complex I polypeptides by immunopurification + MS PMID:12611891.
• Present in respiratory supercomplexes/megacomplex (I2III2IV2) resolved by cryo-EM, which "reveals the precise assignment of individual subunits of human CI" PMID:28844695; NDUFA10 subunit assignment in these structures underlies the ComplexPortal CI membership (GO:0045271, IPI/IDA).
• Reactome models NDUFA10 as a constituent of mature Complex I and of the catalytic reaction "Complex I oxidises NADH to NAD+, reduces CoQ to CoQH2" [reactome:R-HSA-163217]; the R-HSA-6799178/6799179/6799191/6799196/6799197/6799202 reactions describe the stepwise Complex I biogenesis pathway in which the mature complex forms.

PTM

• PTM line: "Phosphorylation at Ser-250 by PINK1 is required for the binding and/or reduction of the complex I substrate ubiquinone." (ECO:0000250|UniProtKB:Q99LC3 — by similarity to mouse) [file:human/NDUFA10/NDUFA10-uniprot.txt "Phosphorylation at Ser-250 by PINK1"]. This links NDUFA10 phospho-regulation to complex I ubiquinone handling but is a by-similarity inference, not human-experimental.

Disease

• Biallelic NDUFA10 variants cause Mitochondrial complex I deficiency, nuclear type 22 (MC1DN22), autosomal recessive; phenotypes include Leigh syndrome [file:human/NDUFA10/NDUFA10-uniprot.txt "Mitochondrial complex I deficiency, nuclear type 22 (MC1DN22)"].
• First disease report: compound-heterozygous NDUFA10 mutations in a Leigh patient; patient fibroblasts showed "decreased amount and activity, and a disturbed assembly of complex I" — directly supporting an assembly/structural role for NDUFA10 (PubMed:21150889; not in GOA/publications cache, PubMed metadata verified). DOI
• Additional variant (Pro-294) reported in a comprehensive mitochondrial-disease genomic study (PubMed:26741492). DOI
• (These two disease papers are UniProt references but are NOT in the GOA table, so they are not reviewed as existing_annotations.)

Annotation-review summary (rationale)

• Structural/complex-membership annotations (GO:0045271 respiratory chain complex I, part_of; via IDA/IPI/IBA/NAS/IEA): well supported — NDUFA10 is a bona fide stable subunit → ACCEPT the experimentally-supported ones (IDA PMID:12611891, PMID:27626371; IPI PMID:28844695), KEEP others.
• Localization: GO:0005743 (mitochondrial inner membrane, IDA ComplexPortal) is the best-supported location → ACCEPT; GO:0005739 (mitochondrion HTP) ACCEPT as coarse/non-core; GO:0005759 (mitochondrial matrix, IEA-SubCell) KEEP_AS_NON_CORE (topological, less precise than inner membrane); Reactome GO:0005743 TAS entries ACCEPT/KEEP.
• Process annotations GO:0006120 (mito electron transport NADH→ubiquinone) and GO:0009060 / GO:0042776 / GO:1902600: these are complex-level processes. NDUFA10 contributes as a structural subunit → KEEP_AS_NON_CORE (accessory, not itself catalytic); GO:0006120 is the closest to core and can be ACCEPTed as a contributing role. GO:1902600 (proton transmembrane transport, IEA GO_REF:0000108 inferred from GO:0008137) is a mechanistic over-reach for an accessory subunit → MARK_AS_OVER_ANNOTATED.
• MF GO:0008137 NADH dehydrogenase (ubiquinone) activity, enables, NAS PMID:9878551: this is the whole-complex catalytic activity. NDUFA10 is explicitly non-catalytic; enables on an accessory subunit is an over-annotation (should be contributes_to at most) → MARK_AS_OVER_ANNOTATED. Do NOT convert to a kinase MF.
• cytoplasm (GO:0005737, IBA): over-broad; the protein is mitochondrial (inner membrane) → MARK_AS_OVER_ANNOTATED (coarse localization; not removed since IBA).

Core functions (final)

• MF: GO:0005198 structural molecule activity (honest MF for a non-catalytic structural subunit).
• MF contribution: contributes_to GO:0008137 NADH dehydrogenase (ubiquinone) activity (complex-level catalysis it helps constitute).
• CC: part_of GO:0045271 respiratory chain complex I (and located_in GO:0005743 mitochondrial inner membrane).
• BP: GO:0006120 mitochondrial electron transport, NADH to ubiquinone and GO:0032981 mitochondrial respiratory chain complex I assembly (assembly/structural role supported by KO and disease-fibroblast assembly defects).