{"gene":"NDUFA6","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2014,"finding":"NDUFA6 (NB4M/LYRM6) anchors the mitochondrial acyl carrier protein subunit ACPM1 within complex I; chromosomal deletion of the gene in Yarrowia lipolytica caused concomitant loss of ACPM1 from the enzyme complex and abolished ubiquinone reductase activity. Mutation of the LYR motif and an associated conserved phenylalanine to alanines also abolished activity and ACPM1 binding. Single-particle electron microscopy and structural modeling showed that NB4M and ACPM1 form a subdomain protruding from the peripheral arm near central subunits involved in catalytic control.","method":"Chromosomal gene deletion in Y. lipolytica, site-directed mutagenesis of LYR motif, ubiquinone reductase activity assay, single-particle electron microscopy, structural modeling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzyme activity assay combined with genetic deletion, mutagenesis, and single-particle EM structural validation in one rigorous study","pmids":["24706851"],"is_preprint":false},{"year":2020,"finding":"Accessory subunit LYRM6 (NDUFA6) stabilizes the TMH1-2ND3 loop of core subunit ND3, which is pivotal for energy conversion by complex I. High-resolution cryo-EM structure of the inactive F89A LYRM6 mutant in Y. lipolytica complex I revealed long-range structural changes affecting the entire conserved loop cluster (NDUFS2 β1-β2 loop, ND1 TMH5-6 loop, ND3 TMH1-2 loop). Atomistic MD simulations of the mutant showed conformational transitions in the loop cluster that disrupted a putative pathway for delivery of substrate protons required for quinone redox chemistry.","method":"Site-directed mutagenesis (F89A), cryo-EM structure determination of mutant complex I, atomistic molecular dynamics simulations","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution structure of functional mutant combined with MD simulations and activity measurements, single study with multiple orthogonal methods","pmids":["33243981"],"is_preprint":false},{"year":2018,"finding":"Bi-allelic loss-of-function variants in NDUFA6 cause early-onset isolated mitochondrial complex I deficiency in children. Functional studies in patient fibroblasts showed complex I assembly defects; mass-spectrometry-based complexome profiling confirmed marked reduction of incorporated NDUFA6 and concomitant reduction of Q-module subunits NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction with wild-type NDUFA6 normalized complex I. Data also supported formation of an ~830 kDa P- and Q-module intermediate in complex with assembled complex III and IV holoenzymes despite lacking the N-module.","method":"Next-generation sequencing, complexome profiling by mass spectrometry, lentiviral complementation of patient fibroblasts, blue-native PAGE","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (complexome profiling, genetic complementation, BN-PAGE) in patient-derived cells across four independent cases","pmids":["30245030"],"is_preprint":false},{"year":2015,"finding":"AAV2-mediated overexpression of NDUFA6 in the visual system of EAE mice rescued retinal complex I activity completely, prevented axonal and retinal ganglion cell loss, and reduced apoptosis; immunoprecipitation and blue-native PAGE confirmed integration of exogenous NDUFA6Flag into endogenous murine complex I.","method":"Intravitreal AAV2 gene delivery, spectrophotometric complex I activity assay, immunoprecipitation, blue-native PAGE, RT-PCR, immunoblotting, PERG, OCT","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo complementation with confirmed complex I integration and functional rescue, single lab, multiple readouts","pmids":["25613946"],"is_preprint":false},{"year":2021,"finding":"A missense variant rs1801311 in the first exon of NDUFA6 disrupts binding of transcription factors YY1, TAF1, and POLR2A at the locus, and physically interacts with the NAGA gene to regulate NAGA expression in the human brain, thereby conferring schizophrenia risk; the risk allele (G) is associated with higher NAGA expression.","method":"Electrophoretic mobility shift assay / ChIP for TF binding, eQTL analysis, Hi-C chromatin interaction data, transcriptome analysis, replication in large Chinese cohort","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genomic and functional assays (TF binding disruption, chromatin interaction, eQTL) from a single lab; mechanistic link to NAGA expression validated by expression analysis","pmids":["33931730"],"is_preprint":false},{"year":2025,"finding":"Ceramide(d18:1/18:1) (CER) binds directly to the RC-I subunit NDUFA6 in mitochondria to inactivate respiratory complex I, thereby reducing reactive oxygen species production in liver ischemia/reperfusion-injured mouse liver. ACER3 ablation and exogenous CER(d18:1/18:1) treatment elevated mitochondrial CER levels, and the CER-NDUFA6 interaction was identified as the mechanistic basis for RC-I inactivation.","method":"Hepatocyte-specific and global Acer3 knockout mice, CER(d18:1/18:1) treatment, lipid-protein binding assay (CER binding to NDUFA6), mitochondria-associated membrane fractionation, ROS measurement, liver I/R injury model","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct lipid-protein binding assay identifying NDUFA6 as CER interactor combined with genetic KO and functional RC-I activity readout; single lab","pmids":["40244698"],"is_preprint":false}],"current_model":"NDUFA6 (LYRM6/NB4M/CI-B14) is a 15 kDa LYR-motif-containing accessory subunit of mitochondrial respiratory complex I that anchors the mitochondrial acyl carrier protein (ACPM1/NDUFAB1) to the Q-module of the peripheral arm, and stabilizes the TMH1-2 loop of core subunit ND3 to maintain the conserved loop cluster geometry essential for proton-coupled ubiquinone reductase activity; loss of NDUFA6 disrupts Q-module assembly and abolishes complex I catalytic activity, while ceramide(d18:1/18:1) can bind NDUFA6 to inactivate complex I and limit ROS production under stress conditions."},"narrative":{"mechanistic_narrative":"NDUFA6 (LYRM6/NB4M) is a LYR-motif accessory subunit of mitochondrial respiratory complex I that is essential for assembly and catalytic function of the enzyme's peripheral arm [PMID:24706851, PMID:30245030]. Through its LYR motif and a conserved phenylalanine, NDUFA6 anchors the mitochondrial acyl carrier protein ACPM1 to form a subdomain protruding from the peripheral arm near catalytic core subunits; loss of NDUFA6 or LYR-motif mutation abolishes ACPM1 binding and ubiquinone reductase activity [PMID:24706851]. Structurally, NDUFA6 stabilizes the TMH1-2 loop of core subunit ND3, and its disruption propagates long-range conformational changes across the conserved loop cluster (NDUFS2, ND1, ND3) that disrupt the proton-delivery pathway required for quinone redox chemistry [PMID:33243981]. In patients, bi-allelic loss-of-function variants in NDUFA6 cause early-onset isolated complex I deficiency, with Q-module assembly defects and concomitant loss of NDUFAB1, NDUFA7, and NDUFA12 that are corrected by wild-type NDUFA6 complementation [PMID:30245030]. Beyond its structural role, NDUFA6 is a target for regulatory inactivation: ceramide(d18:1/18:1) binds NDUFA6 directly to inactivate complex I and limit ROS production during liver ischemia/reperfusion injury [PMID:40244698].","teleology":[{"year":2014,"claim":"Established the molecular function of NDUFA6 by showing it anchors the acyl carrier protein ACPM1 to complex I and is required for catalytic activity, defining its role as a structural accessory subunit rather than a passive component.","evidence":"Chromosomal gene deletion, LYR-motif mutagenesis, ubiquinone reductase assay, and single-particle EM in Yarrowia lipolytica","pmids":["24706851"],"confidence":"High","gaps":["Did not resolve atomic-level mechanism of how ACPM1 anchoring couples to catalysis","Mechanism in mammalian complex I inferred from yeast ortholog"]},{"year":2015,"claim":"Demonstrated in vivo functional relevance by showing AAV-delivered NDUFA6 integrates into endogenous complex I and rescues neuronal complex I activity and survival, establishing its incorporation and functional sufficiency in a mammalian disease model.","evidence":"Intravitreal AAV2 gene delivery in EAE mice with complex I activity assays, immunoprecipitation, BN-PAGE, and PERG/OCT readouts","pmids":["25613946"],"confidence":"Medium","gaps":["Single lab and single disease context (EAE optic neuropathy)","Does not address whether endogenous NDUFA6 levels are limiting in this model"]},{"year":2018,"claim":"Connected NDUFA6 loss to human disease by showing bi-allelic loss-of-function variants cause isolated complex I deficiency through Q-module assembly defects, establishing it as a disease gene and clarifying which subunits depend on it.","evidence":"NGS, complexome profiling by mass spectrometry, lentiviral complementation of patient fibroblasts, and BN-PAGE across four cases","pmids":["30245030"],"confidence":"High","gaps":["Precise step at which Q-module assembly stalls not fully resolved","Genotype-phenotype correlation across patients not detailed"]},{"year":2020,"claim":"Resolved the structural mechanism of how NDUFA6 supports catalysis by showing it stabilizes the ND3 TMH1-2 loop and that its mutation triggers long-range distortion of the conserved loop cluster blocking proton delivery.","evidence":"F89A mutagenesis, cryo-EM structure of mutant complex I, and atomistic MD simulations in Y. lipolytica","pmids":["33243981"],"confidence":"High","gaps":["Proton-delivery pathway is a computational inference requiring direct validation","Conducted in yeast complex I"]},{"year":2021,"claim":"Implicated the NDUFA6 locus in non-mitochondrial regulation by showing a first-exon variant alters transcription factor binding and chromatin looping to control NAGA expression and schizophrenia risk, distinguishing locus-level genomic effects from the protein's mitochondrial function.","evidence":"EMSA/ChIP, eQTL analysis, Hi-C chromatin interaction data, and replication in a Chinese cohort","pmids":["33931730"],"confidence":"Medium","gaps":["Effect is on neighboring NAGA, not on NDUFA6 protein function","Causal pathway from NAGA expression to schizophrenia not established"]},{"year":2025,"claim":"Revealed a regulatory ligand for NDUFA6 by showing ceramide(d18:1/18:1) binds it directly to inactivate complex I and suppress ROS, establishing NDUFA6 as a lipid-sensing node for stress-dependent complex I control.","evidence":"Acer3 knockout mice, ceramide treatment, lipid-protein binding assay, MAM fractionation, and ROS measurement in a liver I/R injury model","pmids":["40244698"],"confidence":"Medium","gaps":["Binding site and structural basis of ceramide-NDUFA6 interaction not defined","Single lab; physiological generality beyond liver I/R unknown"]},{"year":null,"claim":"How NDUFA6-mediated ACPM1 anchoring and ND3 loop stabilization are dynamically regulated by lipids such as ceramide during stress remains unresolved at the structural and mechanistic level.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the ceramide-bound NDUFA6 state","Link between lipid-driven inactivation and assembly role not integrated","Mammalian-specific structural data largely absent from the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,5]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2]}],"complexes":["Mitochondrial respiratory complex I"],"partners":["NDUFAB1","ND3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P56556","full_name":"NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6","aliases":["Complex I-B14","CI-B14","LYR motif-containing protein 6","NADH-ubiquinone oxidoreductase B14 subunit"],"length_aa":128,"mass_kda":15.1,"function":"Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed to be not involved in catalysis. Required for proper complex I assembly (PubMed:30245030). 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 inner membrane","url":"https://www.uniprot.org/uniprotkb/P56556/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NDUFA6","classification":"Common Essential","n_dependent_lines":643,"n_total_lines":1208,"dependency_fraction":0.5322847682119205},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NDUFA6","total_profiled":1310},"omim":[{"mim_id":"618253","title":"MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 33; MC1DN33","url":"https://www.omim.org/entry/618253"},{"mim_id":"602141","title":"NADH-UBIQUINONE OXIDOREDUCTASE Fe-S PROTEIN 8; NDUFS8","url":"https://www.omim.org/entry/602141"},{"mim_id":"602140","title":"NADH-UBIQUINONE OXIDOREDUCTASE SUBUNIT B8; NDUFB8","url":"https://www.omim.org/entry/602140"},{"mim_id":"602139","title":"NADH-UBIQUINONE OXIDOREDUCTASE SUBUNIT A7; NDUFA7","url":"https://www.omim.org/entry/602139"},{"mim_id":"602138","title":"NADH-UBIQUINONE OXIDOREDUCTASE SUBUNIT A6; NDUFA6","url":"https://www.omim.org/entry/602138"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"End piece","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NDUFA6"},"hgnc":{"alias_symbol":["B14","LYRM6","CI-B14","NADHB14"],"prev_symbol":[]},"alphafold":{"accession":"P56556","domains":[{"cath_id":"-","chopping":"24-109","consensus_level":"high","plddt":94.683,"start":24,"end":109}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P56556","model_url":"https://alphafold.ebi.ac.uk/files/AF-P56556-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P56556-F1-predicted_aligned_error_v6.png","plddt_mean":87.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NDUFA6","jax_strain_url":"https://www.jax.org/strain/search?query=NDUFA6"},"sequence":{"accession":"P56556","fasta_url":"https://rest.uniprot.org/uniprotkb/P56556.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P56556/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P56556"}},"corpus_meta":[{"pmid":"8133536","id":"PMC_8133536","title":"Endometrial cancer in 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Mutation of the LYR motif and an associated conserved phenylalanine to alanines also abolished activity and ACPM1 binding. Single-particle electron microscopy and structural modeling showed that NB4M and ACPM1 form a subdomain protruding from the peripheral arm near central subunits involved in catalytic control.\",\n      \"method\": \"Chromosomal gene deletion in Y. lipolytica, site-directed mutagenesis of LYR motif, ubiquinone reductase activity assay, single-particle electron microscopy, structural modeling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzyme activity assay combined with genetic deletion, mutagenesis, and single-particle EM structural validation in one rigorous study\",\n      \"pmids\": [\"24706851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Accessory subunit LYRM6 (NDUFA6) stabilizes the TMH1-2ND3 loop of core subunit ND3, which is pivotal for energy conversion by complex I. High-resolution cryo-EM structure of the inactive F89A LYRM6 mutant in Y. lipolytica complex I revealed long-range structural changes affecting the entire conserved loop cluster (NDUFS2 β1-β2 loop, ND1 TMH5-6 loop, ND3 TMH1-2 loop). Atomistic MD simulations of the mutant showed conformational transitions in the loop cluster that disrupted a putative pathway for delivery of substrate protons required for quinone redox chemistry.\",\n      \"method\": \"Site-directed mutagenesis (F89A), cryo-EM structure determination of mutant complex I, atomistic molecular dynamics simulations\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution structure of functional mutant combined with MD simulations and activity measurements, single study with multiple orthogonal methods\",\n      \"pmids\": [\"33243981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Bi-allelic loss-of-function variants in NDUFA6 cause early-onset isolated mitochondrial complex I deficiency in children. Functional studies in patient fibroblasts showed complex I assembly defects; mass-spectrometry-based complexome profiling confirmed marked reduction of incorporated NDUFA6 and concomitant reduction of Q-module subunits NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction with wild-type NDUFA6 normalized complex I. Data also supported formation of an ~830 kDa P- and Q-module intermediate in complex with assembled complex III and IV holoenzymes despite lacking the N-module.\",\n      \"method\": \"Next-generation sequencing, complexome profiling by mass spectrometry, lentiviral complementation of patient fibroblasts, blue-native PAGE\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (complexome profiling, genetic complementation, BN-PAGE) in patient-derived cells across four independent cases\",\n      \"pmids\": [\"30245030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AAV2-mediated overexpression of NDUFA6 in the visual system of EAE mice rescued retinal complex I activity completely, prevented axonal and retinal ganglion cell loss, and reduced apoptosis; immunoprecipitation and blue-native PAGE confirmed integration of exogenous NDUFA6Flag into endogenous murine complex I.\",\n      \"method\": \"Intravitreal AAV2 gene delivery, spectrophotometric complex I activity assay, immunoprecipitation, blue-native PAGE, RT-PCR, immunoblotting, PERG, OCT\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo complementation with confirmed complex I integration and functional rescue, single lab, multiple readouts\",\n      \"pmids\": [\"25613946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A missense variant rs1801311 in the first exon of NDUFA6 disrupts binding of transcription factors YY1, TAF1, and POLR2A at the locus, and physically interacts with the NAGA gene to regulate NAGA expression in the human brain, thereby conferring schizophrenia risk; the risk allele (G) is associated with higher NAGA expression.\",\n      \"method\": \"Electrophoretic mobility shift assay / ChIP for TF binding, eQTL analysis, Hi-C chromatin interaction data, transcriptome analysis, replication in large Chinese cohort\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genomic and functional assays (TF binding disruption, chromatin interaction, eQTL) from a single lab; mechanistic link to NAGA expression validated by expression analysis\",\n      \"pmids\": [\"33931730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ceramide(d18:1/18:1) (CER) binds directly to the RC-I subunit NDUFA6 in mitochondria to inactivate respiratory complex I, thereby reducing reactive oxygen species production in liver ischemia/reperfusion-injured mouse liver. ACER3 ablation and exogenous CER(d18:1/18:1) treatment elevated mitochondrial CER levels, and the CER-NDUFA6 interaction was identified as the mechanistic basis for RC-I inactivation.\",\n      \"method\": \"Hepatocyte-specific and global Acer3 knockout mice, CER(d18:1/18:1) treatment, lipid-protein binding assay (CER binding to NDUFA6), mitochondria-associated membrane fractionation, ROS measurement, liver I/R injury model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct lipid-protein binding assay identifying NDUFA6 as CER interactor combined with genetic KO and functional RC-I activity readout; single lab\",\n      \"pmids\": [\"40244698\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NDUFA6 (LYRM6/NB4M/CI-B14) is a 15 kDa LYR-motif-containing accessory subunit of mitochondrial respiratory complex I that anchors the mitochondrial acyl carrier protein (ACPM1/NDUFAB1) to the Q-module of the peripheral arm, and stabilizes the TMH1-2 loop of core subunit ND3 to maintain the conserved loop cluster geometry essential for proton-coupled ubiquinone reductase activity; loss of NDUFA6 disrupts Q-module assembly and abolishes complex I catalytic activity, while ceramide(d18:1/18:1) can bind NDUFA6 to inactivate complex I and limit ROS production under stress conditions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NDUFA6 (LYRM6/NB4M) is a LYR-motif accessory subunit of mitochondrial respiratory complex I that is essential for assembly and catalytic function of the enzyme's peripheral arm [#0, #2]. Through its LYR motif and a conserved phenylalanine, NDUFA6 anchors the mitochondrial acyl carrier protein ACPM1 to form a subdomain protruding from the peripheral arm near catalytic core subunits; loss of NDUFA6 or LYR-motif mutation abolishes ACPM1 binding and ubiquinone reductase activity [#0]. Structurally, NDUFA6 stabilizes the TMH1-2 loop of core subunit ND3, and its disruption propagates long-range conformational changes across the conserved loop cluster (NDUFS2, ND1, ND3) that disrupt the proton-delivery pathway required for quinone redox chemistry [#1]. In patients, bi-allelic loss-of-function variants in NDUFA6 cause early-onset isolated complex I deficiency, with Q-module assembly defects and concomitant loss of NDUFAB1, NDUFA7, and NDUFA12 that are corrected by wild-type NDUFA6 complementation [#2]. Beyond its structural role, NDUFA6 is a target for regulatory inactivation: ceramide(d18:1/18:1) binds NDUFA6 directly to inactivate complex I and limit ROS production during liver ischemia/reperfusion injury [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the molecular function of NDUFA6 by showing it anchors the acyl carrier protein ACPM1 to complex I and is required for catalytic activity, defining its role as a structural accessory subunit rather than a passive component.\",\n      \"evidence\": \"Chromosomal gene deletion, LYR-motif mutagenesis, ubiquinone reductase assay, and single-particle EM in Yarrowia lipolytica\",\n      \"pmids\": [\"24706851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not resolve atomic-level mechanism of how ACPM1 anchoring couples to catalysis\",\n        \"Mechanism in mammalian complex I inferred from yeast ortholog\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated in vivo functional relevance by showing AAV-delivered NDUFA6 integrates into endogenous complex I and rescues neuronal complex I activity and survival, establishing its incorporation and functional sufficiency in a mammalian disease model.\",\n      \"evidence\": \"Intravitreal AAV2 gene delivery in EAE mice with complex I activity assays, immunoprecipitation, BN-PAGE, and PERG/OCT readouts\",\n      \"pmids\": [\"25613946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab and single disease context (EAE optic neuropathy)\",\n        \"Does not address whether endogenous NDUFA6 levels are limiting in this model\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected NDUFA6 loss to human disease by showing bi-allelic loss-of-function variants cause isolated complex I deficiency through Q-module assembly defects, establishing it as a disease gene and clarifying which subunits depend on it.\",\n      \"evidence\": \"NGS, complexome profiling by mass spectrometry, lentiviral complementation of patient fibroblasts, and BN-PAGE across four cases\",\n      \"pmids\": [\"30245030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise step at which Q-module assembly stalls not fully resolved\",\n        \"Genotype-phenotype correlation across patients not detailed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the structural mechanism of how NDUFA6 supports catalysis by showing it stabilizes the ND3 TMH1-2 loop and that its mutation triggers long-range distortion of the conserved loop cluster blocking proton delivery.\",\n      \"evidence\": \"F89A mutagenesis, cryo-EM structure of mutant complex I, and atomistic MD simulations in Y. lipolytica\",\n      \"pmids\": [\"33243981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Proton-delivery pathway is a computational inference requiring direct validation\",\n        \"Conducted in yeast complex I\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated the NDUFA6 locus in non-mitochondrial regulation by showing a first-exon variant alters transcription factor binding and chromatin looping to control NAGA expression and schizophrenia risk, distinguishing locus-level genomic effects from the protein's mitochondrial function.\",\n      \"evidence\": \"EMSA/ChIP, eQTL analysis, Hi-C chromatin interaction data, and replication in a Chinese cohort\",\n      \"pmids\": [\"33931730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Effect is on neighboring NAGA, not on NDUFA6 protein function\",\n        \"Causal pathway from NAGA expression to schizophrenia not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a regulatory ligand for NDUFA6 by showing ceramide(d18:1/18:1) binds it directly to inactivate complex I and suppress ROS, establishing NDUFA6 as a lipid-sensing node for stress-dependent complex I control.\",\n      \"evidence\": \"Acer3 knockout mice, ceramide treatment, lipid-protein binding assay, MAM fractionation, and ROS measurement in a liver I/R injury model\",\n      \"pmids\": [\"40244698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding site and structural basis of ceramide-NDUFA6 interaction not defined\",\n        \"Single lab; physiological generality beyond liver I/R unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NDUFA6-mediated ACPM1 anchoring and ND3 loop stabilization are dynamically regulated by lipids such as ceramide during stress remains unresolved at the structural and mechanistic level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structure of the ceramide-bound NDUFA6 state\",\n        \"Link between lipid-driven inactivation and assembly role not integrated\",\n        \"Mammalian-specific structural data largely absent from the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\n      \"Mitochondrial respiratory complex I\"\n    ],\n    \"partners\": [\n      \"NDUFAB1\",\n      \"ND3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}