Affinage

NDUFA10

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial · UniProt O95299

Round 2 corrected
Length
355 aa
Mass
40.8 kDa
Annotated
2026-04-29
43 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NDUFA10 is an accessory subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase) that is strictly required for Complex I assembly, ubiquinone-reductive activity, and mitochondrial ATP production. PINK1 phosphorylates NDUFA10 at Ser-250, and this modification is necessary for Complex I ubiquinone reduction; phosphomimetic NDUFA10 rescues Complex I deficits, ATP synthesis, and synaptic transmission in PINK1-null Drosophila and patient-derived cells (PMID:24652937, PMID:25412178). Beyond its Complex I structural role, NDUFA10 harbors a deoxyribonucleoside kinase domain that sequesters dGTP and serves as the primary determinant of mitochondrial dGTP levels, linking oxidative phosphorylation to mitochondrial DNA precursor homeostasis (PMID:35739187). Compound-heterozygous loss-of-function mutations in NDUFA10 cause mitochondrial Complex I deficiency in patients (PMID:21150889).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2005 High

    Identification that NDUFA10 is a phosphoprotein established post-translational regulation of a Complex I accessory subunit, raising the question of which kinase(s) and which site(s) are functionally relevant.

    Evidence 2D gel electrophoresis and tandem MS/MS on bovine heart mitochondrial Complex I, with synthetic peptide confirmation of phospho-Ser-59

    PMID:15848193

    Open questions at the time
    • The responsible kinase was not identified
    • Functional consequence of Ser-59 phosphorylation on Complex I activity was not tested
    • Relevance of this site in non-bovine systems was unknown
  2. 2010 Medium

    Establishing that patient mutations in NDUFA10 cause deficient Complex I assembly and activity demonstrated that NDUFA10, although an accessory subunit, is indispensable for Complex I biogenesis.

    Evidence Biochemical analysis (BN-PAGE, activity assays, immunoblotting) of fibroblasts from a patient with compound-heterozygous NDUFA10 mutations

    PMID:21150889

    Open questions at the time
    • Single family study; genetic rescue was not performed
    • The specific assembly step blocked by NDUFA10 loss was not resolved
  3. 2014 High

    Discovery that PINK1 phosphorylates NDUFA10 at Ser-250 and that this event is required for ubiquinone reduction provided a direct mechanistic link between PINK1-associated Parkinson's disease and Complex I dysfunction.

    Evidence Phosphoproteomics of Complex I from Pink1−/− mouse tissues; phosphomimetic S250D rescue of Complex I activity, ATP synthesis, and neurotransmission in PINK1-null Drosophila and patient cells

    PMID:24652937 PMID:25412178

    Open questions at the time
    • Whether Ser-250 phosphorylation is the sole functional PINK1 target on Complex I or one of several
    • Structural basis of how phospho-Ser-250 enables ubiquinone reduction was not determined
    • Degree to which NDUFA10 rescue acts independently of the Parkin/mitophagy axis was debated across studies
  4. 2016 High

    CRISPR knockout confirmed that NDUFA10 is strictly required for Complex I assembly in human cells and that its loss destabilizes subunits within the same structural module, resolving ambiguity from patient studies.

    Evidence CRISPR/Cas9 knockout in human cell lines with BN-PAGE and quantitative proteomics

    PMID:27626371

    Open questions at the time
    • Which specific assembly intermediate accumulates upon NDUFA10 loss was not fully resolved
    • Potential extra-Complex I functions were not addressed
  5. 2022 High

    Identification of a deoxyribonucleoside kinase domain in NDUFA10 that tightly binds dGTP and controls ~50% of mitochondrial dGTP content revealed an unexpected moonlighting function linking oxidative metabolism to mtDNA precursor homeostasis.

    Evidence Site-directed mutagenesis (E160A/R161A) in HEK-293T cells; in vitro dGTP-binding assay; HPLC measurement of mitochondrial dNTP pools; BN-PAGE confirming intact Complex I assembly

    PMID:35739187

    Open questions at the time
    • Whether NDUFA10's dNK domain possesses catalytic kinase activity or acts solely as a sequestering/storage site
    • Impact of dGTP-binding mutations on mtDNA replication fidelity or copy number in vivo
    • Relationship between phosphorylation at Ser-250 and dGTP binding
  6. 2024 Medium

    Identification of CAV3 and neuroglobin as physical interactors of NDUFA10 that protect it from degradation and sustain Complex I function expanded the regulatory network controlling NDUFA10 stability in disease contexts (diabetic cardiomyopathy and Parkinson's models).

    Evidence Co-immunoprecipitation and LC-MS/MS interactomics; AAV-mediated CAV3 overexpression in db/db mouse hearts; Ngb overexpression/knockdown with Complex I activity and apoptosis readouts in MN9D cells

    PMID:38671439 PMID:39454716

    Open questions at the time
    • Binding interfaces on NDUFA10 for CAV3 and neuroglobin are unmapped
    • Whether these interactions occur on assembled Complex I or on free NDUFA10
    • Independent replication needed for both interactions
  7. 2025 Medium

    In vivo knockdown of NDUFA10 in mouse medial prefrontal cortex demonstrated that NDUFA10-dependent ATP production is required for normal cortical excitability, extending its physiological relevance to brain circuit function.

    Evidence Site-specific viral knockdown in mPFC; in vivo ATP fiber-optic recording; EEG; ATP rescue

    PMID:40415484

    Open questions at the time
    • Whether the phenotype is specific to NDUFA10 or generalizes to any Complex I subunit loss
    • Long-term neurological consequences of mPFC NDUFA10 depletion not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of how Ser-250 phosphorylation activates ubiquinone reduction, whether the dNK domain possesses catalytic kinase activity or functions purely as a dGTP-sequestering module, and how NDUFA10's dual roles in electron transfer and dNTP homeostasis are coordinated.
  • No high-resolution structure of NDUFA10 with bound dGTP or phospho-Ser-250 exists
  • Catalytic vs. sequestering function of the dNK domain unresolved
  • Coordination between phosphorylation state and dGTP binding not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0008289 lipid binding 1
Localization
GO:0005739 mitochondrion 5
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-1643685 Disease 2
Partners
CAV3NGBPINK1
Complex memberships
Mitochondrial Complex I (NADH:ubiquinone oxidoreductase)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Phosphorylation of NDUFA10 (the 42-kDa subunit of mitochondrial Complex I) was mapped by tandem mass spectrometry to serine-59 within the peptide LITVDGNICSGKSK (residues 47–60) in bovine heart mitochondria. 2D gel electrophoresis combined with tandem mass spectrometry (MS/MS), confirmed by synthetic peptide FEBS letters High 15848193
2008 Two-dimensional electrophoresis and extensive MS/MS analysis of rat brain NDUFA10 identified a D/N substitution at position 120 (from a 353A/G coding transition) as the biochemical difference between two major isoforms, and found 33 distinct post-translational modifications at 59 residues, including methylations of R, K, and H and likely acetylations at the C-terminal region; residues C67, H149, and H322 were particularly targeted, suggesting functional importance. 2-DE combined with MS/MS; synthetic variant verification Proteomics Medium 18442173
2010 Compound-heterozygous mutations in NDUFA10 (one disrupting the start codon, one causing an amino acid substitution) cause decreased Complex I amount, activity, and disturbed assembly in patient fibroblasts, establishing NDUFA10 as an accessory subunit required for proper Complex I assembly and activity. Patient fibroblast biochemical assays (BN-PAGE, activity measurements, immunoblotting); genetic sequencing European journal of human genetics Medium 21150889
2014 PINK1 phosphorylates NDUFA10 at serine-250, and this phosphorylation is required for ubiquinone reduction by Complex I. Loss of PINK1 leads to specific loss of Ser-250 phosphorylation on NdufA10, causing reduced Complex I reductive activity and decreased mitochondrial membrane potential. Phosphomimetic NdufA10 (S250D) rescues Complex I deficits, ATP synthesis, mitochondrial depolarization, and synaptic transmission defects in PINK1-null Drosophila and patient-derived cells. Phosphoproteomics of Complex I from Pink1−/− mouse liver/brain; phosphomimetic rescue in knockout cells and Drosophila; ATP synthesis and membrane potential assays Science High 24652937
2014 In Drosophila pink1 mutants, transgenic overexpression of ND42 (NDUFA10 ortholog) or its co-chaperone sicily restores Complex I activity and partially rescues locomotion and mitochondrial defects in flight muscles, independent of mitophagy; this rescue does not strictly require Ser-250 phosphorylation. NDUFA10 knockdown only minimally affects CCCP-induced mitophagy in human cells, and NDUFA10 overexpression does not restore Parkin mitochondrial translocation upon PINK1 loss, indicating the rescue acts via Complex I activity rather than the Parkin/mitophagy pathway. Drosophila transgenic overexpression; RNAi screen in Drosophila cells; CCCP-induced mitophagy assay in human cells; Complex I activity assays; behavioral assays PLoS genetics High 25412178
2016 CRISPR/Cas9 knockout of NDUFA10 in human cells results in loss of assembled, functional Complex I, demonstrating that NDUFA10 is strictly required for Complex I assembly; quantitative proteomics showed that loss of NDUFA10 destabilizes subunits in the same structural module. CRISPR/Cas9 gene editing in human cell lines; BN-PAGE; quantitative proteomics Nature High 27626371
2022 NDUFA10 harbors a deoxyribonucleoside kinase (dNK) domain that tightly binds dGTP; mutation of this domain (E160A/R161A) reduces dGTP binding in vitro and lowers mitochondrial dGTP content by ~50% without disrupting Complex I assembly or activity, establishing NDUFA10 as the primary determinant of mitochondrial dGTP levels and linking oxidative metabolism to mitochondrial DNA maintenance. Site-directed mutagenesis in HEK-293T cells; in vitro dGTP-binding assay; measurement of mitochondrial dNTP pools by HPLC; BN-PAGE for Complex I assembly Communications biology High 35739187
2022 Benzo[a]pyrene (via its metabolite BPDE) downregulates NDUFA10 expression in mouse Leydig cells through PPARα activation, and NDUFA10-mediated mitochondrial dysfunction perturbs testosterone synthesis; NDUFA10 knockdown recapitulates mitochondrial impairment and steroidogenesis perturbation in TM3 cells. In vivo mouse model; transcriptome profiling; in vitro siRNA knockdown in TM3 cells; mitochondrial function assays; in silico toxicological analyses Ecotoxicology and environmental safety Medium 36108438
2024 CAV3 (caveolin-3) physically interacts with NDUFA10 as shown by co-immunoprecipitation; CAV3 overexpression reduces lysosomal degradation of NDUFA10, restores Complex I activity, and ameliorates mitochondrial dysfunction in diabetic cardiomyopathy models, while loss of CAV3 exacerbates NDUFA10 degradation and Complex I impairment. LC-MS/MS interactome; co-immunoprecipitation; cardiac-specific AAV overexpression in db/db mice; Complex I activity assays; mitochondrial function assays Journal of translational medicine Medium 38671439
2024 Neuroglobin (Ngb) physically interacts with NDUFA10 (confirmed by co-immunoprecipitation in MN9D cells); Ngb overexpression rescues Complex I activity, restores mitochondrial membrane potential and NAD+/NADH ratios, reduces ROS, and inhibits caspase-9-mediated apoptosis in an MPP+-induced Parkinson's disease cell model, while Ngb knockdown worsens these parameters. Co-immunoprecipitation; lentiviral overexpression and siRNA knockdown; ELISA-based Complex I activity; flow cytometry (apoptosis); MMP and ROS measurements Neuroscience Medium 39454716
2024 PINK1 regulates ATP production by phosphorylating the Complex I subunit NdufA10; the PD-associated PINK1-G411S mutant shows increased kinase stability due to altered ATP-binding pocket rigidity (revealed by molecular dynamics), and enhances mitochondrial-linked functions including NdufA10 phosphorylation. Molecular dynamics simulation; biochemical characterization of PINK1 mutants; mitochondrial function assays bioRxiv (preprint)preprint Low bio_10.1101_2024.06.28.601304
2025 Viral knockdown of NDUFA10 in the medial prefrontal cortex (mPFC) of mice reduces ATP levels and increases sevoflurane-induced burst suppression ratio and EEG suppression time, while exogenous ATP administration reverses these effects, establishing that NDUFA10-driven energy metabolism in the mPFC is required for normal cortical excitability under anesthesia. Site-specific viral knockdown; in vivo fiber-optic ATP recording; EEG recording; mRNA sequencing; ATP administration rescue CNS neuroscience & therapeutics Medium 40415484

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Genome-scale RNAi screen for host factors required for HIV replication. Cell host & microbe 627 18976975
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2003 Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. Nature biotechnology 485 12665801
2016 Accessory subunits are integral for assembly and function of human mitochondrial complex I. Nature 450 27626371
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2017 Architecture of Human Mitochondrial Respiratory Megacomplex I2III2IV2. Cell 391 28844695
2011 The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors. PLoS pathogens 341 22046132
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2014 PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling. Science (New York, N.Y.) 274 24652937
2022 Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell 256 35063084
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2013 The functional interactome landscape of the human histone deacetylase family. Molecular systems biology 235 23752268
2016 Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function. Molecular cell 220 27499296
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2018 Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes. Essays in biochemistry 206 30030361
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2020 AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Signal Transduction System. Molecular cell 152 31995728
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2018 Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains. Molecular cell 136 30554943
2014 The central role of EED in the orchestration of polycomb group complexes. Nature communications 131 24457600
2010 NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease. European journal of human genetics : EJHG 68 21150889
2014 The complex I subunit NDUFA10 selectively rescues Drosophila pink1 mutants through a mechanism independent of mitophagy. PLoS genetics 61 25412178
2005 Mass spectrometric identification of a novel phosphorylation site in subunit NDUFA10 of bovine mitochondrial complex I. FEBS letters 54 15848193
2023 An Exploration of the Coherent Effects between METTL3 and NDUFA10 on Alzheimer's Disease. International journal of molecular sciences 18 37373264
2022 Benzo[a]pyrene inhibits testosterone biosynthesis via NDUFA10-mediated mitochondrial compromise in mouse Leydig cells: Integrating experimental and in silico toxicological approaches. Ecotoxicology and environmental safety 18 36108438
2022 Most mitochondrial dGTP is tightly bound to respiratory complex I through the NDUFA10 subunit. Communications biology 16 35739187
2008 Mass spectrometric characterization of mitochondrial complex I NDUFA10 variants. Proteomics 16 18442173
2024 CAV3 alleviates diabetic cardiomyopathy via inhibiting NDUFA10-mediated mitochondrial dysfunction. Journal of translational medicine 15 38671439
2017 Widening the Heterogeneity of Leigh Syndrome: Clinical, Biochemical, and Neuroradiologic Features in a Patient Harboring a NDUFA10 Mutation. JIMD reports 14 28247337
2024 Neuroglobin protects dopaminergic neurons in a Parkinson's cell model by interacting with mitochondrial complex NDUFA10. Neuroscience 6 39454716
2025 NDUFA10-Mediated ATP Reduction in Medial Prefrontal Cortex Exacerbates Burst Suppression in Aged Mice. CNS neuroscience & therapeutics 1 40415484
2026 NDUFA10: An Emerging Oncogenic Driver of Metastasis in Lung Adenocarcinoma. Current cancer drug targets 0 41944119