{"gene":"NDUFA10","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2014,"finding":"PINK1 phosphorylates serine-250 of NdufA10 (NDUFA10), and this phosphorylation is required for ubiquinone reduction by mitochondrial complex I. Loss of PINK1 causes specific loss of this phosphorylation, leading to complex I reductive activity deficiency and decreased mitochondrial membrane potential. Phosphomimetic NdufA10 rescues complex I deficits, ATP synthesis, mitochondrial depolarization, and synaptic transmission defects in both mouse knockout cells and Drosophila pink1-null mutants.","method":"Phosphoproteomics of complex I from Pink1(-/-) mouse liver and brain; phosphomimetic mutagenesis; rescue experiments in mouse knockout cells and Drosophila pink1-null mutants; ATP synthesis assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phosphosite identified by mass spectrometry, functional consequence validated by mutagenesis, rescue experiments in two model organisms (mouse KO cells and Drosophila), multiple orthogonal methods","pmids":["24652937"],"is_preprint":false},{"year":2014,"finding":"Overexpression of Drosophila ND42 (NDUFA10 ortholog) or its co-chaperone sicily restores complex I activity and partially rescues locomotion and mitochondrial defects in Drosophila pink1 mutants, but fails to rescue parkin mutant phenotypes, indicating the rescue is specific to PINK1-dependent complex I regulation and is independent of mitophagy. NDUFA10 knockdown in human cells only minimally affects CCCP-induced mitophagy, and NDUFA10 overexpression does not restore Parkin mitochondrial translocation upon PINK1 loss.","method":"Transgenic overexpression in Drosophila pink1 and parkin mutants; RNAi knockdown; mitophagy assays (CCCP-induced); Parkin translocation assays; complex I activity assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic rescue experiments in Drosophila combined with human cell knockdown/overexpression and functional assays, independently replicating and extending the Science 2014 findings","pmids":["25412178"],"is_preprint":false},{"year":2005,"finding":"Mass spectrometry identified serine-59 (within peptide LITVDGNICSGKSK, residues 47–60) as a phosphorylation site in NDUFA10 from bovine heart mitochondria complex I.","method":"Tandem mass spectrometry (MS/MS) of bovine heart mitochondrial complex I; peptide synthesis confirmation","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct phosphosite identification by MS/MS with synthetic peptide confirmation, single lab but rigorous method","pmids":["15848193"],"is_preprint":false},{"year":2010,"finding":"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 a structural/assembly subunit required for complex I integrity.","method":"Genetic screening of NDUFA10 in patient fibroblasts and muscle; biochemical assays of complex I amount, activity, and assembly (BN-PAGE)","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cell biochemistry with assembly and activity assays, single lab, no mutagenesis reconstitution","pmids":["21150889"],"is_preprint":false},{"year":2022,"finding":"NDUFA10 contains a deoxyribonucleoside kinase (dNK) domain that directly binds dGTP. Mutation of this domain (E160A/R161A) reduces dGTP binding capacity in vitro and causes a ~50% reduction in mitochondrial dGTP content without disrupting complex I assembly or activity, demonstrating that NDUFA10 sequesters most mitochondrial dGTP via its dNK domain.","method":"dNK domain mutagenesis in HEK-293T cells; in vitro dGTP binding assays; mitochondrial dNTP pool measurements; complex I assembly and activity assays","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay combined with domain mutagenesis and quantitative dNTP pool measurements in human cells, multiple orthogonal methods in single study","pmids":["35739187"],"is_preprint":false},{"year":2008,"finding":"Two-dimensional electrophoresis and MS/MS characterization of NDUFA10 from rat brain identified a D120N amino acid variant arising from a 353A/G coding transition, and mapped 33 post-translational modifications at 59 residues, including methylations and probable acetylations at the C-terminal region and high reactivity at C67, H149, and H322.","method":"2-DE combined with tandem mass spectrometry (MS/MS) of rat brain mitochondrial complex I","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct MS/MS identification of modifications and variants, but functional significance of individual modifications not experimentally validated","pmids":["18442173"],"is_preprint":false},{"year":2024,"finding":"CAV3 (caveolin-3) physically interacts with NDUFA10 (identified by LC-MS/MS and confirmed by co-immunoprecipitation), and CAV3 overexpression reduces lysosomal-pathway degradation of NDUFA10, thereby restoring complex I activity and improving mitochondrial function in diabetic cardiomyopathy.","method":"LC-MS/MS interactome analysis; co-immunoprecipitation; CAV3 cardiac-specific overexpression in db/db mice; complex I activity assays","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP confirmed interaction, in vivo rescue with activity assay, single lab","pmids":["38671439"],"is_preprint":false},{"year":2024,"finding":"Neuroglobin (Ngb) physically interacts with NDUFA10, as confirmed by co-immunoprecipitation in MN9D cells. Ngb overexpression restores complex I activity, mitochondrial membrane potential, and NAD+/NADH ratios, and reduces ROS and apoptosis in an MPP+-based Parkinson's disease cell model; Ngb knockdown has the opposite effects.","method":"Co-immunoprecipitation in MN9D cells; complex I activity (ELISA); mitochondrial membrane potential; NAD+/NADH ratio; ROS measurement; flow cytometry apoptosis assay","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-IP plus multiple functional readouts, single lab","pmids":["39454716"],"is_preprint":false},{"year":2026,"finding":"The astrocytic dopamine D2 receptor (Drd2) regulates mitochondrial complex I activity by recruiting scaffold protein β-arrestin2, which facilitates interaction of β-arrestin2 with both NDUFA4 and NDUFA10 (complex I subunits). Selective knockdown of NDUFA10 in mouse astrocytes completely abolishes the neuroprotective effect of Drd2 activation in vivo.","method":"Transcriptome sequencing; metabolomics; co-immunoprecipitation (β-arrestin2 with NDUFA4/NDUFA10); astrocyte-selective viral knockdown of NDUFA10 in mouse PD model; complex I activity assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirmed interaction, in vivo knockdown epistasis with functional readout, single lab","pmids":["42174197"],"is_preprint":false},{"year":2024,"finding":"The PINK1-G411S mutant retains the ability to phosphorylate NdufA10 and regulate ATP production via complex I, with molecular dynamics simulations indicating the mutation increases rigidity and stability of PINK1's ATP-binding pocket, enhancing kinase function.","method":"Molecular dynamics simulations; functional characterization of PINK1 mutant kinase activity toward NdufA10 in cell-based assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 4 / Weak — primarily computational (molecular dynamics), abstract does not detail direct in vitro kinase assay with NdufA10 substrate; preprint not peer-reviewed","pmids":["bio_10.1101_2024.06.28.601304"],"is_preprint":true},{"year":2025,"finding":"Site-specific viral knockdown of NDUFA10 in mouse medial prefrontal cortex (mPFC) reduces ATP levels and increases sevoflurane-induced burst suppression; exogenous ATP administration attenuates these changes, placing NDUFA10-dependent complex I activity upstream of cortical ATP availability and anesthesia sensitivity.","method":"Stereotaxic viral knockdown; in vivo fiber-optic ATP monitoring; EEG burst suppression recording; RNA sequencing","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo site-specific knockdown with functional EEG and ATP readouts, single lab, single study","pmids":["40415484"],"is_preprint":false}],"current_model":"NDUFA10 is an accessory subunit of mitochondrial respiratory complex I whose deoxyribonucleoside kinase (dNK) domain sequesters the majority of mitochondrial dGTP; its phosphorylation at serine-250 by PINK1 is required for ubiquinone reduction by complex I, linking PINK1 kinase activity to complex I electron transfer and ATP synthesis; NDUFA10 additionally interacts with CAV3, neuroglobin, and β-arrestin2 (downstream of dopamine D2 receptor), all of which modulate complex I activity through NDUFA10, and loss-of-function mutations in NDUFA10 impair complex I assembly and cause mitochondrial disease (Leigh syndrome)."},"narrative":{"mechanistic_narrative":"NDUFA10 is an accessory/assembly subunit of mitochondrial respiratory complex I required for complex I integrity and electron transfer, and through it for ATP synthesis and mitochondrial membrane potential [PMID:24652937, PMID:21150889]. Compound-heterozygous loss-of-function mutations in NDUFA10 reduce complex I amount, activity, and assembly in patient cells, establishing it as a structural subunit needed for complex I assembly [PMID:21150889]. Its activity is gated by regulated phosphorylation: PINK1 phosphorylates serine-250 of NDUFA10, an event required for ubiquinone reduction by complex I, such that loss of PINK1 abolishes this phosphorylation and produces complex I reductive deficiency, membrane depolarization, and synaptic defects that a phosphomimetic NDUFA10 rescues across mouse and Drosophila models [PMID:24652937]. This PINK1–NDUFA10 axis acts independently of mitophagy, rescuing pink1 but not parkin mutant phenotypes [PMID:25412178]. Beyond its complex I role, NDUFA10 carries a deoxyribonucleoside kinase (dNK) domain that directly binds dGTP and sequesters the majority of the mitochondrial dGTP pool, a function separable from complex I assembly and activity [PMID:35739187]. NDUFA10 stability and complex I output are further modulated by physical partners including CAV3, which limits its lysosomal degradation [PMID:38671439], neuroglobin [PMID:39454716], and β-arrestin2 recruited downstream of the dopamine D2 receptor [PMID:42174197]. In neural tissue, NDUFA10-dependent complex I activity sets cortical ATP availability and thereby influences anesthesia sensitivity [PMID:40415484].","teleology":[{"year":2005,"claim":"Before functional regulation was known, it was unclear whether NDUFA10 was post-translationally modified; mapping a phosphosite established that the subunit is a substrate for regulatory modification within complex I.","evidence":"MS/MS of bovine heart mitochondrial complex I with synthetic peptide confirmation identifying phospho-serine-59","pmids":["15848193"],"confidence":"High","gaps":["No kinase identified for this site","Functional consequence of the phosphorylation not tested"]},{"year":2008,"claim":"Extending the modification inventory, broad PTM and variant mapping showed NDUFA10 carries numerous methylations, acetylations, and reactive residues, framing it as a heavily modified subunit.","evidence":"2-DE plus MS/MS of rat brain mitochondrial complex I mapping 33 PTMs at 59 residues and a D120N variant","pmids":["18442173"],"confidence":"Medium","gaps":["Functional significance of individual modifications not validated","No link to complex I activity established"]},{"year":2010,"claim":"It was unknown whether NDUFA10 is essential for complex I; patient mutations demonstrated it is a structural/assembly subunit required for complex I integrity and a cause of mitochondrial disease.","evidence":"Genetic screening of patient fibroblasts/muscle with BN-PAGE assembly and activity assays of compound-heterozygous mutations","pmids":["21150889"],"confidence":"Medium","gaps":["No mutagenesis reconstitution to prove causality","Assembly intermediate accumulation not resolved","Single lab, limited patient number"]},{"year":2014,"claim":"The mechanism connecting PINK1 to bioenergetics was unknown; phosphorylation of NDUFA10 serine-250 by PINK1 was shown to be required for ubiquinone reduction, linking PINK1 kinase activity directly to complex I electron transfer.","evidence":"Phosphoproteomics of Pink1(-/-) mouse tissue plus phosphomimetic mutagenesis and rescue in mouse KO cells and Drosophila pink1 nulls","pmids":["24652937"],"confidence":"High","gaps":["Direct in vitro kinase assay on isolated NDUFA10 not shown","Structural basis of how S250 phosphorylation enables Q reduction unresolved"]},{"year":2014,"claim":"Whether the PINK1–NDUFA10 axis operated through mitophagy was open; genetic epistasis established the rescue is mitophagy-independent and specific to PINK1-dependent complex I regulation.","evidence":"Transgenic ND42/sicily overexpression in Drosophila pink1 vs parkin mutants, human cell knockdown, and CCCP mitophagy/Parkin translocation assays","pmids":["25412178"],"confidence":"High","gaps":["Mechanism distinguishing PINK1 substrate selection from Parkin pathway unresolved","Co-chaperone sicily contribution to human NDUFA10 not defined"]},{"year":2022,"claim":"The function of NDUFA10's dNK domain was unknown; it was shown to directly bind and sequester most of the mitochondrial dGTP pool, a moonlighting role separable from complex I assembly.","evidence":"dNK domain mutagenesis (E160A/R161A) in HEK-293T, in vitro dGTP binding, and mitochondrial dNTP pool measurements","pmids":["35739187"],"confidence":"High","gaps":["Physiological consequence of dGTP sequestration not established","Whether dGTP binding feeds back on complex I function untested"]},{"year":2024,"claim":"Regulators controlling NDUFA10 abundance were unknown; CAV3 was identified as a direct partner that limits lysosomal degradation of NDUFA10 to preserve complex I activity in diabetic cardiomyopathy.","evidence":"LC-MS/MS interactome, reciprocal co-IP, and CAV3 cardiac overexpression in db/db mice with complex I activity assays","pmids":["38671439"],"confidence":"Medium","gaps":["Degradation machinery routing NDUFA10 to lysosomes not defined","Single lab"]},{"year":2024,"claim":"Whether neuroglobin acts on complex I via NDUFA10 was unknown; co-IP and functional rescue placed Ngb as an NDUFA10 partner supporting complex I activity in a Parkinson's cell model.","evidence":"Co-IP in MN9D cells plus complex I activity, membrane potential, NAD+/NADH, ROS, and apoptosis readouts with Ngb knockdown/overexpression","pmids":["39454716"],"confidence":"Medium","gaps":["Single co-IP without reciprocal validation in this context","Direct vs indirect interaction not resolved"]},{"year":2026,"claim":"The downstream effector of astrocytic dopamine D2 receptor neuroprotection was unclear; β-arrestin2 was shown to bridge Drd2 signaling to NDUFA10, with NDUFA10 knockdown abolishing the neuroprotective effect.","evidence":"Transcriptomics, metabolomics, β-arrestin2 co-IP with NDUFA4/NDUFA10, and astrocyte-selective NDUFA10 knockdown in a mouse PD model","pmids":["42174197"],"confidence":"Medium","gaps":["Whether β-arrestin2 alters NDUFA10 phosphorylation or stability unknown","Single lab"]},{"year":2025,"claim":"Whether NDUFA10 sets tissue-level energy state was untested; site-specific knockdown showed NDUFA10-dependent complex I activity is upstream of cortical ATP availability and anesthesia sensitivity.","evidence":"Stereotaxic viral knockdown in mouse mPFC with in vivo ATP monitoring, EEG burst suppression, and ATP rescue","pmids":["40415484"],"confidence":"Medium","gaps":["Cell-type specificity of the effect not fully resolved","Link to PINK1 phosphorylation in this context not tested"]},{"year":null,"claim":"It remains unresolved how the multiple regulatory inputs (PINK1 phosphorylation, dGTP sequestration, CAV3/Ngb/β-arrestin2 partners) are integrated to set complex I output, and whether they act through shared or independent mechanisms.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of S250 phosphorylation effect on complex I","Physiological role of dGTP sequestration unknown","Cross-talk among the named partners untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,3]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,6]}],"complexes":["mitochondrial respiratory complex I"],"partners":["PINK1","CAV3","NGB","ARRB2","NDUFA4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95299","full_name":"NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial","aliases":["Complex I-42kD","CI-42kD","NADH-ubiquinone oxidoreductase 42 kDa subunit"],"length_aa":355,"mass_kda":40.8,"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","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/O95299/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NDUFA10","classification":"Not Classified","n_dependent_lines":328,"n_total_lines":1208,"dependency_fraction":0.271523178807947},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTR2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NDUFA10","total_profiled":1310},"omim":[{"mim_id":"618243","title":"MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 22; MC1DN22","url":"https://www.omim.org/entry/618243"},{"mim_id":"608309","title":"PTEN-INDUCED KINASE 1; PINK1","url":"https://www.omim.org/entry/608309"},{"mim_id":"603843","title":"NADH-UBIQUINONE OXIDOREDUCTASE SUBUNIT B10; NDUFB10","url":"https://www.omim.org/entry/603843"},{"mim_id":"603840","title":"NADH-UBIQUINONE OXIDOREDUCTASE SUBUNIT B4; NDUFB4","url":"https://www.omim.org/entry/603840"},{"mim_id":"603835","title":"NADH-UBIQUINONE OXIDOREDUCTASE SUBUNIT A10; NDUFA10","url":"https://www.omim.org/entry/603835"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"tongue","ntpm":309.9}],"url":"https://www.proteinatlas.org/search/NDUFA10"},"hgnc":{"alias_symbol":["CI-42k"],"prev_symbol":[]},"alphafold":{"accession":"O95299","domains":[{"cath_id":"3.40.50.300","chopping":"55-323","consensus_level":"medium","plddt":90.1487,"start":55,"end":323}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95299","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95299-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95299-F1-predicted_aligned_error_v6.png","plddt_mean":84.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NDUFA10","jax_strain_url":"https://www.jax.org/strain/search?query=NDUFA10"},"sequence":{"accession":"O95299","fasta_url":"https://rest.uniprot.org/uniprotkb/O95299.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95299/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95299"}},"corpus_meta":[{"pmid":"24652937","id":"PMC_24652937","title":"PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling.","date":"2014","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24652937","citation_count":276,"is_preprint":false},{"pmid":"21150889","id":"PMC_21150889","title":"NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease.","date":"2010","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/21150889","citation_count":68,"is_preprint":false},{"pmid":"25412178","id":"PMC_25412178","title":"The complex I subunit NDUFA10 selectively rescues Drosophila pink1 mutants through a mechanism independent of mitophagy.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25412178","citation_count":62,"is_preprint":false},{"pmid":"15848193","id":"PMC_15848193","title":"Mass spectrometric identification of a novel phosphorylation site in subunit NDUFA10 of bovine mitochondrial complex I.","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/15848193","citation_count":54,"is_preprint":false},{"pmid":"36108438","id":"PMC_36108438","title":"Benzo[a]pyrene inhibits testosterone biosynthesis via NDUFA10-mediated mitochondrial compromise in mouse Leydig cells: Integrating experimental and in silico toxicological approaches.","date":"2022","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/36108438","citation_count":19,"is_preprint":false},{"pmid":"37373264","id":"PMC_37373264","title":"An Exploration of the Coherent Effects between METTL3 and NDUFA10 on Alzheimer's Disease.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37373264","citation_count":18,"is_preprint":false},{"pmid":"35739187","id":"PMC_35739187","title":"Most mitochondrial dGTP is tightly bound to respiratory complex I through the NDUFA10 subunit.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/35739187","citation_count":17,"is_preprint":false},{"pmid":"18442173","id":"PMC_18442173","title":"Mass spectrometric characterization of mitochondrial complex I NDUFA10 variants.","date":"2008","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/18442173","citation_count":16,"is_preprint":false},{"pmid":"38671439","id":"PMC_38671439","title":"CAV3 alleviates diabetic cardiomyopathy via inhibiting NDUFA10-mediated mitochondrial dysfunction.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38671439","citation_count":15,"is_preprint":false},{"pmid":"28247337","id":"PMC_28247337","title":"Widening the Heterogeneity of Leigh Syndrome: Clinical, Biochemical, and Neuroradiologic Features in a Patient Harboring a NDUFA10 Mutation.","date":"2017","source":"JIMD reports","url":"https://pubmed.ncbi.nlm.nih.gov/28247337","citation_count":14,"is_preprint":false},{"pmid":"39454716","id":"PMC_39454716","title":"Neuroglobin protects dopaminergic neurons in a Parkinson's cell model by interacting with mitochondrial complex NDUFA10.","date":"2024","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39454716","citation_count":10,"is_preprint":false},{"pmid":"40415484","id":"PMC_40415484","title":"NDUFA10-Mediated ATP Reduction in Medial Prefrontal Cortex Exacerbates Burst Suppression in Aged Mice.","date":"2025","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/40415484","citation_count":1,"is_preprint":false},{"pmid":"41944119","id":"PMC_41944119","title":"NDUFA10: An Emerging Oncogenic Driver of Metastasis in Lung Adenocarcinoma.","date":"2026","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/41944119","citation_count":0,"is_preprint":false},{"pmid":"42174197","id":"PMC_42174197","title":"Neuroprotective effect of astrocytic dopamine Drd2 receptor on mitochondrial complex I in a mouse model of Parkinson's disease through β-arrestin2-NDUFA10 regulation.","date":"2026","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/42174197","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.06.28.601304","title":"PINK1-G411S mutant increases kinase stability and enhances mitochondrial-linked functions","date":"2024-07-01","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.28.601304","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9391,"output_tokens":2931,"usd":0.036069,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10359,"output_tokens":3495,"usd":0.069585,"stage2_stop_reason":"end_turn"},"total_usd":0.105654,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"PINK1 phosphorylates serine-250 of NdufA10 (NDUFA10), and this phosphorylation is required for ubiquinone reduction by mitochondrial complex I. Loss of PINK1 causes specific loss of this phosphorylation, leading to complex I reductive activity deficiency and decreased mitochondrial membrane potential. Phosphomimetic NdufA10 rescues complex I deficits, ATP synthesis, mitochondrial depolarization, and synaptic transmission defects in both mouse knockout cells and Drosophila pink1-null mutants.\",\n      \"method\": \"Phosphoproteomics of complex I from Pink1(-/-) mouse liver and brain; phosphomimetic mutagenesis; rescue experiments in mouse knockout cells and Drosophila pink1-null mutants; ATP synthesis assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phosphosite identified by mass spectrometry, functional consequence validated by mutagenesis, rescue experiments in two model organisms (mouse KO cells and Drosophila), multiple orthogonal methods\",\n      \"pmids\": [\"24652937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Overexpression of Drosophila ND42 (NDUFA10 ortholog) or its co-chaperone sicily restores complex I activity and partially rescues locomotion and mitochondrial defects in Drosophila pink1 mutants, but fails to rescue parkin mutant phenotypes, indicating the rescue is specific to PINK1-dependent complex I regulation and is independent of mitophagy. NDUFA10 knockdown in human cells only minimally affects CCCP-induced mitophagy, and NDUFA10 overexpression does not restore Parkin mitochondrial translocation upon PINK1 loss.\",\n      \"method\": \"Transgenic overexpression in Drosophila pink1 and parkin mutants; RNAi knockdown; mitophagy assays (CCCP-induced); Parkin translocation assays; complex I activity assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic rescue experiments in Drosophila combined with human cell knockdown/overexpression and functional assays, independently replicating and extending the Science 2014 findings\",\n      \"pmids\": [\"25412178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mass spectrometry identified serine-59 (within peptide LITVDGNICSGKSK, residues 47–60) as a phosphorylation site in NDUFA10 from bovine heart mitochondria complex I.\",\n      \"method\": \"Tandem mass spectrometry (MS/MS) of bovine heart mitochondrial complex I; peptide synthesis confirmation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct phosphosite identification by MS/MS with synthetic peptide confirmation, single lab but rigorous method\",\n      \"pmids\": [\"15848193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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 a structural/assembly subunit required for complex I integrity.\",\n      \"method\": \"Genetic screening of NDUFA10 in patient fibroblasts and muscle; biochemical assays of complex I amount, activity, and assembly (BN-PAGE)\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cell biochemistry with assembly and activity assays, single lab, no mutagenesis reconstitution\",\n      \"pmids\": [\"21150889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NDUFA10 contains a deoxyribonucleoside kinase (dNK) domain that directly binds dGTP. Mutation of this domain (E160A/R161A) reduces dGTP binding capacity in vitro and causes a ~50% reduction in mitochondrial dGTP content without disrupting complex I assembly or activity, demonstrating that NDUFA10 sequesters most mitochondrial dGTP via its dNK domain.\",\n      \"method\": \"dNK domain mutagenesis in HEK-293T cells; in vitro dGTP binding assays; mitochondrial dNTP pool measurements; complex I assembly and activity assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay combined with domain mutagenesis and quantitative dNTP pool measurements in human cells, multiple orthogonal methods in single study\",\n      \"pmids\": [\"35739187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Two-dimensional electrophoresis and MS/MS characterization of NDUFA10 from rat brain identified a D120N amino acid variant arising from a 353A/G coding transition, and mapped 33 post-translational modifications at 59 residues, including methylations and probable acetylations at the C-terminal region and high reactivity at C67, H149, and H322.\",\n      \"method\": \"2-DE combined with tandem mass spectrometry (MS/MS) of rat brain mitochondrial complex I\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct MS/MS identification of modifications and variants, but functional significance of individual modifications not experimentally validated\",\n      \"pmids\": [\"18442173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CAV3 (caveolin-3) physically interacts with NDUFA10 (identified by LC-MS/MS and confirmed by co-immunoprecipitation), and CAV3 overexpression reduces lysosomal-pathway degradation of NDUFA10, thereby restoring complex I activity and improving mitochondrial function in diabetic cardiomyopathy.\",\n      \"method\": \"LC-MS/MS interactome analysis; co-immunoprecipitation; CAV3 cardiac-specific overexpression in db/db mice; complex I activity assays\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP confirmed interaction, in vivo rescue with activity assay, single lab\",\n      \"pmids\": [\"38671439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Neuroglobin (Ngb) physically interacts with NDUFA10, as confirmed by co-immunoprecipitation in MN9D cells. Ngb overexpression restores complex I activity, mitochondrial membrane potential, and NAD+/NADH ratios, and reduces ROS and apoptosis in an MPP+-based Parkinson's disease cell model; Ngb knockdown has the opposite effects.\",\n      \"method\": \"Co-immunoprecipitation in MN9D cells; complex I activity (ELISA); mitochondrial membrane potential; NAD+/NADH ratio; ROS measurement; flow cytometry apoptosis assay\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-IP plus multiple functional readouts, single lab\",\n      \"pmids\": [\"39454716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The astrocytic dopamine D2 receptor (Drd2) regulates mitochondrial complex I activity by recruiting scaffold protein β-arrestin2, which facilitates interaction of β-arrestin2 with both NDUFA4 and NDUFA10 (complex I subunits). Selective knockdown of NDUFA10 in mouse astrocytes completely abolishes the neuroprotective effect of Drd2 activation in vivo.\",\n      \"method\": \"Transcriptome sequencing; metabolomics; co-immunoprecipitation (β-arrestin2 with NDUFA4/NDUFA10); astrocyte-selective viral knockdown of NDUFA10 in mouse PD model; complex I activity assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirmed interaction, in vivo knockdown epistasis with functional readout, single lab\",\n      \"pmids\": [\"42174197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The PINK1-G411S mutant retains the ability to phosphorylate NdufA10 and regulate ATP production via complex I, with molecular dynamics simulations indicating the mutation increases rigidity and stability of PINK1's ATP-binding pocket, enhancing kinase function.\",\n      \"method\": \"Molecular dynamics simulations; functional characterization of PINK1 mutant kinase activity toward NdufA10 in cell-based assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — primarily computational (molecular dynamics), abstract does not detail direct in vitro kinase assay with NdufA10 substrate; preprint not peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.06.28.601304\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Site-specific viral knockdown of NDUFA10 in mouse medial prefrontal cortex (mPFC) reduces ATP levels and increases sevoflurane-induced burst suppression; exogenous ATP administration attenuates these changes, placing NDUFA10-dependent complex I activity upstream of cortical ATP availability and anesthesia sensitivity.\",\n      \"method\": \"Stereotaxic viral knockdown; in vivo fiber-optic ATP monitoring; EEG burst suppression recording; RNA sequencing\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo site-specific knockdown with functional EEG and ATP readouts, single lab, single study\",\n      \"pmids\": [\"40415484\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NDUFA10 is an accessory subunit of mitochondrial respiratory complex I whose deoxyribonucleoside kinase (dNK) domain sequesters the majority of mitochondrial dGTP; its phosphorylation at serine-250 by PINK1 is required for ubiquinone reduction by complex I, linking PINK1 kinase activity to complex I electron transfer and ATP synthesis; NDUFA10 additionally interacts with CAV3, neuroglobin, and β-arrestin2 (downstream of dopamine D2 receptor), all of which modulate complex I activity through NDUFA10, and loss-of-function mutations in NDUFA10 impair complex I assembly and cause mitochondrial disease (Leigh syndrome).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NDUFA10 is an accessory/assembly subunit of mitochondrial respiratory complex I required for complex I integrity and electron transfer, and through it for ATP synthesis and mitochondrial membrane potential [#0, #3]. Compound-heterozygous loss-of-function mutations in NDUFA10 reduce complex I amount, activity, and assembly in patient cells, establishing it as a structural subunit needed for complex I assembly [#3]. Its activity is gated by regulated phosphorylation: PINK1 phosphorylates serine-250 of NDUFA10, an event required for ubiquinone reduction by complex I, such that loss of PINK1 abolishes this phosphorylation and produces complex I reductive deficiency, membrane depolarization, and synaptic defects that a phosphomimetic NDUFA10 rescues across mouse and Drosophila models [#0]. This PINK1–NDUFA10 axis acts independently of mitophagy, rescuing pink1 but not parkin mutant phenotypes [#1]. Beyond its complex I role, NDUFA10 carries a deoxyribonucleoside kinase (dNK) domain that directly binds dGTP and sequesters the majority of the mitochondrial dGTP pool, a function separable from complex I assembly and activity [#4]. NDUFA10 stability and complex I output are further modulated by physical partners including CAV3, which limits its lysosomal degradation [#6], neuroglobin [#7], and β-arrestin2 recruited downstream of the dopamine D2 receptor [#8]. In neural tissue, NDUFA10-dependent complex I activity sets cortical ATP availability and thereby influences anesthesia sensitivity [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Before functional regulation was known, it was unclear whether NDUFA10 was post-translationally modified; mapping a phosphosite established that the subunit is a substrate for regulatory modification within complex I.\",\n      \"evidence\": \"MS/MS of bovine heart mitochondrial complex I with synthetic peptide confirmation identifying phospho-serine-59\",\n      \"pmids\": [\"15848193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No kinase identified for this site\", \"Functional consequence of the phosphorylation not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extending the modification inventory, broad PTM and variant mapping showed NDUFA10 carries numerous methylations, acetylations, and reactive residues, framing it as a heavily modified subunit.\",\n      \"evidence\": \"2-DE plus MS/MS of rat brain mitochondrial complex I mapping 33 PTMs at 59 residues and a D120N variant\",\n      \"pmids\": [\"18442173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of individual modifications not validated\", \"No link to complex I activity established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"It was unknown whether NDUFA10 is essential for complex I; patient mutations demonstrated it is a structural/assembly subunit required for complex I integrity and a cause of mitochondrial disease.\",\n      \"evidence\": \"Genetic screening of patient fibroblasts/muscle with BN-PAGE assembly and activity assays of compound-heterozygous mutations\",\n      \"pmids\": [\"21150889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis reconstitution to prove causality\", \"Assembly intermediate accumulation not resolved\", \"Single lab, limited patient number\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The mechanism connecting PINK1 to bioenergetics was unknown; phosphorylation of NDUFA10 serine-250 by PINK1 was shown to be required for ubiquinone reduction, linking PINK1 kinase activity directly to complex I electron transfer.\",\n      \"evidence\": \"Phosphoproteomics of Pink1(-/-) mouse tissue plus phosphomimetic mutagenesis and rescue in mouse KO cells and Drosophila pink1 nulls\",\n      \"pmids\": [\"24652937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vitro kinase assay on isolated NDUFA10 not shown\", \"Structural basis of how S250 phosphorylation enables Q reduction unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Whether the PINK1–NDUFA10 axis operated through mitophagy was open; genetic epistasis established the rescue is mitophagy-independent and specific to PINK1-dependent complex I regulation.\",\n      \"evidence\": \"Transgenic ND42/sicily overexpression in Drosophila pink1 vs parkin mutants, human cell knockdown, and CCCP mitophagy/Parkin translocation assays\",\n      \"pmids\": [\"25412178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing PINK1 substrate selection from Parkin pathway unresolved\", \"Co-chaperone sicily contribution to human NDUFA10 not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The function of NDUFA10's dNK domain was unknown; it was shown to directly bind and sequester most of the mitochondrial dGTP pool, a moonlighting role separable from complex I assembly.\",\n      \"evidence\": \"dNK domain mutagenesis (E160A/R161A) in HEK-293T, in vitro dGTP binding, and mitochondrial dNTP pool measurements\",\n      \"pmids\": [\"35739187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of dGTP sequestration not established\", \"Whether dGTP binding feeds back on complex I function untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Regulators controlling NDUFA10 abundance were unknown; CAV3 was identified as a direct partner that limits lysosomal degradation of NDUFA10 to preserve complex I activity in diabetic cardiomyopathy.\",\n      \"evidence\": \"LC-MS/MS interactome, reciprocal co-IP, and CAV3 cardiac overexpression in db/db mice with complex I activity assays\",\n      \"pmids\": [\"38671439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation machinery routing NDUFA10 to lysosomes not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether neuroglobin acts on complex I via NDUFA10 was unknown; co-IP and functional rescue placed Ngb as an NDUFA10 partner supporting complex I activity in a Parkinson's cell model.\",\n      \"evidence\": \"Co-IP in MN9D cells plus complex I activity, membrane potential, NAD+/NADH, ROS, and apoptosis readouts with Ngb knockdown/overexpression\",\n      \"pmids\": [\"39454716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single co-IP without reciprocal validation in this context\", \"Direct vs indirect interaction not resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The downstream effector of astrocytic dopamine D2 receptor neuroprotection was unclear; β-arrestin2 was shown to bridge Drd2 signaling to NDUFA10, with NDUFA10 knockdown abolishing the neuroprotective effect.\",\n      \"evidence\": \"Transcriptomics, metabolomics, β-arrestin2 co-IP with NDUFA4/NDUFA10, and astrocyte-selective NDUFA10 knockdown in a mouse PD model\",\n      \"pmids\": [\"42174197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether β-arrestin2 alters NDUFA10 phosphorylation or stability unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether NDUFA10 sets tissue-level energy state was untested; site-specific knockdown showed NDUFA10-dependent complex I activity is upstream of cortical ATP availability and anesthesia sensitivity.\",\n      \"evidence\": \"Stereotaxic viral knockdown in mouse mPFC with in vivo ATP monitoring, EEG burst suppression, and ATP rescue\",\n      \"pmids\": [\"40415484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type specificity of the effect not fully resolved\", \"Link to PINK1 phosphorylation in this context not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the multiple regulatory inputs (PINK1 phosphorylation, dGTP sequestration, CAV3/Ngb/β-arrestin2 partners) are integrated to set complex I output, and whether they act through shared or independent mechanisms.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of S250 phosphorylation effect on complex I\", \"Physiological role of dGTP sequestration unknown\", \"Cross-talk among the named partners untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"complexes\": [\"mitochondrial respiratory complex I\"],\n    \"partners\": [\"PINK1\", \"CAV3\", \"NGB\", \"ARRB2\", \"NDUFA4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}