{"gene":"NDUFA7","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2007,"finding":"NDUFA7 (B14.5a) is a phosphorylated subunit of bovine heart mitochondrial complex I, as detected by mass spectrometry following nondenaturing gel electrophoretic separation and phosphopeptide enrichment with titanium dioxide.","method":"Native PAGE separation of complex I, in-gel digestion, TiO2 phosphopeptide enrichment, MS/MS","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct MS detection of phosphorylation in purified complex I, single lab, single method","pmids":["17443843"],"is_preprint":false},{"year":2015,"finding":"NDUFA7 is succinylated in mouse heart mitochondria; succinylation of NDUFA7 is uniquely detected in Sirt5-knockout (but not wild-type) hearts, indicating that SIRT5 acts as a desuccinylase that removes succinyl modifications from NDUFA7.","method":"Affinity enrichment of succinylated peptides, LC-MS/MS proteomics, comparison of WT vs. Sirt5−/− mouse heart mitochondria","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MS-based PTM identification in KO vs WT, single lab, single method, no direct enzymatic reconstitution","pmids":["26388266"],"is_preprint":false},{"year":2018,"finding":"NDUFA7 is a subunit of the Q-module of mitochondrial complex I; loss of NDUFA6 (a related Q-module subunit) leads to a concomitant reduction in incorporated NDUFA7 along with other Q-module subunits (NDUFAB1, NDUFA12), as shown by complexome profiling.","method":"Mass-spectrometry-based complexome profiling of patient fibroblast cell lines with bi-allelic NDUFA6 variants; lentiviral transduction rescue","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complexome profiling with rescue experiment, single lab, two orthogonal methods (complexome profiling + lentiviral complementation)","pmids":["30245030"],"is_preprint":false},{"year":1997,"finding":"The NDUFA7 gene (encoding complex I subunit B14.5a) maps to human chromosome 20p13, as determined by in situ hybridization of isolated genomic clones.","method":"Screening of human cosmid and P1 libraries, fluorescence in situ hybridization (FISH)","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct cytogenetic mapping experiment, single lab, single method","pmids":["9345899"],"is_preprint":false},{"year":2021,"finding":"NDUFA7 physically interacts with the mitochondrial micropeptide MPM; overexpression of MPM inhibits mitochondrial complex I activity, and this inhibitory effect is attenuated by siRNA-mediated knockdown of NDUFA7, placing NDUFA7 as the functional mediator of MPM's effect on complex I.","method":"Co-immunoprecipitation (Co-IP) interaction assay, siRNA knockdown, mitochondrial complex I activity assay, NAD+/NADH ratio measurement","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional epistasis (MPM effect rescued by NDUFA7 KD), Co-IP binding, enzymatic activity assay; single lab","pmids":["34478872"],"is_preprint":false},{"year":2020,"finding":"NDUFA7 depletion in zebrafish embryos causes cardiac development and functional defects, increases expression of pathological hypertrophy biomarkers (nppa/ANP, nppb/BNP), promotes mitochondrial ROS production, and activates calcineurin signalling, establishing a role for NDUFA7 in restraining pathological cardiac hypertrophy via the ROS-calcineurin axis.","method":"Morpholino/siRNA knockdown in zebrafish embryos; cardiac functional assays; ROS measurement; calcineurin signalling assessment; biomarker gene expression (nppa, nppb)","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vivo model with defined molecular phenotype (ROS, calcineurin), single lab, multiple readouts","pmids":["32989924"],"is_preprint":false},{"year":2024,"finding":"NDUFA7 complex I protein levels are reduced in renal tubular cells when miR-3960 (delivered via B-cell-derived extracellular vesicles) targets TRMT5, a mitochondrial tRNA methyltransferase; this places NDUFA7 downstream of TRMT5-dependent mitochondrial tRNA modification in maintaining complex I biogenesis.","method":"Dual-luciferase reporter assay, co-immunoprecipitation, EV blockade experiments, miR-3960 depletion in obesity mouse model","journal":"Small","confidence":"Low","confidence_rationale":"Tier 3 / Weak — NDUFA7 reduction is an indirect downstream readout; direct mechanistic link to NDUFA7 not experimentally interrogated beyond protein level changes","pmids":["38958071"],"is_preprint":false}],"current_model":"NDUFA7 (B14.5a) is a structural subunit of the Q-module of mitochondrial respiratory chain complex I that is phosphorylated and succinylated (the latter regulated by the deacylase SIRT5); it physically interacts with the micropeptide MPM to modulate complex I activity and the NAD+/NADH ratio, and its loss triggers ROS overproduction and calcineurin pathway activation leading to pathological cardiac hypertrophy."},"narrative":{"mechanistic_narrative":"NDUFA7 (B14.5a) is a structural subunit of the Q-module of mitochondrial respiratory chain complex I, where its incorporation depends on the integrity of other Q-module subunits and is reduced upon loss of NDUFA6 [PMID:30245030]. The protein carries regulatory post-translational modifications: it is phosphorylated within assembled complex I [PMID:17443843] and succinylated, with the modification accumulating in Sirt5-knockout heart mitochondria, identifying SIRT5 as a desuccinylase acting on NDUFA7 [PMID:26388266]. Functionally, NDUFA7 mediates the inhibitory effect of the mitochondrial micropeptide MPM on complex I activity and the NAD+/NADH ratio, since MPM physically binds NDUFA7 and the inhibition is lost upon NDUFA7 knockdown [PMID:34478872]. Loss of NDUFA7 in vivo causes cardiac developmental and functional defects, drives mitochondrial ROS overproduction and calcineurin signalling, and induces pathological hypertrophy biomarkers, establishing a role in restraining pathological cardiac hypertrophy [PMID:32989924]. The gene maps to human chromosome 20p13 [PMID:9345899].","teleology":[{"year":1997,"claim":"Establishing the genomic location of NDUFA7 provided the foundational locus assignment for the complex I subunit B14.5a.","evidence":"Library screening and FISH mapping of genomic clones","pmids":["9345899"],"confidence":"Medium","gaps":["No functional or structural information about the protein","Gene structure and regulatory elements not characterized"]},{"year":2007,"claim":"Detection of NDUFA7 phosphorylation in purified complex I raised the question of regulatory post-translational control of the subunit.","evidence":"Native PAGE separation, TiO2 phosphopeptide enrichment, MS/MS of bovine heart complex I","pmids":["17443843"],"confidence":"Medium","gaps":["Responsible kinase not identified","Functional consequence of phosphorylation on complex I activity not tested","Phosphosite stoichiometry unknown"]},{"year":2015,"claim":"Identifying NDUFA7 succinylation as SIRT5-regulated connected the subunit to deacylase-dependent metabolic control of complex I.","evidence":"Succinyl-peptide affinity enrichment and LC-MS/MS comparing WT vs Sirt5-/- mouse heart mitochondria","pmids":["26388266"],"confidence":"Medium","gaps":["No direct enzymatic reconstitution of SIRT5 acting on NDUFA7","Effect of succinylation on complex I function not measured","Modified residues' functional roles unresolved"]},{"year":2018,"claim":"Assigning NDUFA7 to the Q-module and showing its co-dependence with NDUFA6 defined its structural position within complex I assembly.","evidence":"Complexome profiling of NDUFA6-variant patient fibroblasts with lentiviral rescue","pmids":["30245030"],"confidence":"Medium","gaps":["Direct NDUFA7-NDUFA6 contacts not mapped structurally","Whether NDUFA7 loss reciprocally destabilizes other subunits not tested here"]},{"year":2020,"claim":"In vivo depletion linked NDUFA7 loss to ROS overproduction, calcineurin activation, and pathological cardiac hypertrophy, giving the subunit a physiological role beyond bioenergetics.","evidence":"Morpholino/siRNA knockdown in zebrafish embryos with cardiac, ROS, and calcineurin readouts","pmids":["32989924"],"confidence":"Medium","gaps":["Mechanistic link between complex I deficiency and calcineurin not dissected","Mammalian cardiac model not tested","Whether effect is cell-autonomous to cardiomyocytes unknown"]},{"year":2021,"claim":"Demonstrating that NDUFA7 mediates the micropeptide MPM's inhibition of complex I identified a direct partner controlling complex I activity and NAD+/NADH balance.","evidence":"Co-IP, siRNA knockdown epistasis, complex I activity and NAD+/NADH assays","pmids":["34478872"],"confidence":"Medium","gaps":["Binding interface and stoichiometry of MPM-NDUFA7 not defined","Reciprocal validation in additional systems limited","Whether MPM alters NDUFA7 PTM status unknown"]},{"year":2024,"claim":"NDUFA7 protein levels were placed downstream of TRMT5-dependent mitochondrial tRNA modification, implicating it as a readout of complex I biogenesis under EV-microRNA control.","evidence":"Dual-luciferase reporter, Co-IP, EV blockade, miR-3960 depletion in obesity mouse model","pmids":["38958071"],"confidence":"Low","gaps":["NDUFA7 reduction is an indirect downstream readout not mechanistically interrogated","No direct link between TRMT5 and NDUFA7 expression","Specificity to NDUFA7 versus general complex I loss unclear"]},{"year":null,"claim":"How the phosphorylation, succinylation, and MPM-binding inputs are integrated to tune NDUFA7's contribution to complex I activity and downstream ROS/calcineurin signalling remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model placing PTM sites and the MPM interface within complex I","Kinase and direct enzymatic regulators not identified","Causal chain from complex I dysfunction to calcineurin activation not delineated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,4]}],"complexes":["mitochondrial respiratory chain complex I (Q-module)"],"partners":["MPM","NDUFA6","SIRT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95182","full_name":"NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7","aliases":["Complex I-B14.5a","CI-B14.5a","NADH-ubiquinone oxidoreductase subunit B14.5a"],"length_aa":113,"mass_kda":12.6,"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 inner membrane","url":"https://www.uniprot.org/uniprotkb/O95182/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NDUFA7","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NDUFA7","total_profiled":1310},"omim":[{"mim_id":"618202","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 30; DNAJC30","url":"https://www.omim.org/entry/618202"},{"mim_id":"603835","title":"NADH-UBIQUINONE OXIDOREDUCTASE SUBUNIT A10; NDUFA10","url":"https://www.omim.org/entry/603835"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":253.2}],"url":"https://www.proteinatlas.org/search/NDUFA7"},"hgnc":{"alias_symbol":["B14.5a"],"prev_symbol":[]},"alphafold":{"accession":"O95182","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95182","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95182-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95182-F1-predicted_aligned_error_v6.png","plddt_mean":86.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NDUFA7","jax_strain_url":"https://www.jax.org/strain/search?query=NDUFA7"},"sequence":{"accession":"O95182","fasta_url":"https://rest.uniprot.org/uniprotkb/O95182.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95182/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95182"}},"corpus_meta":[{"pmid":"26388266","id":"PMC_26388266","title":"Characterization of the cardiac succinylome and its role in ischemia-reperfusion injury.","date":"2015","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/26388266","citation_count":149,"is_preprint":false},{"pmid":"30245030","id":"PMC_30245030","title":"Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency.","date":"2018","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30245030","citation_count":56,"is_preprint":false},{"pmid":"17443843","id":"PMC_17443843","title":"The phosphorylation pattern of bovine heart complex I subunits.","date":"2007","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/17443843","citation_count":53,"is_preprint":false},{"pmid":"34478872","id":"PMC_34478872","title":"Downregulation of a mitochondrial micropeptide, MPM, promotes hepatoma metastasis by enhancing mitochondrial complex I activity.","date":"2021","source":"Molecular therapy : the journal of the American Society of Gene 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housekeeping genes as internal controls for quantitative RT-PCR analysis of the veined rapa whelk (Rapana venosa).","date":"2017","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/28584723","citation_count":18,"is_preprint":false},{"pmid":"35154017","id":"PMC_35154017","title":"In Vivo and In Vitro Matured Oocytes From Mice of Advanced Reproductive Age Exhibit Alternative Splicing Processes for Mitochondrial Oxidative Phosphorylation.","date":"2022","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/35154017","citation_count":12,"is_preprint":false},{"pmid":"33993545","id":"PMC_33993545","title":"Transcriptome profiles of pre-pubertal and adult in vitro matured ovine oocytes obtained from FSH-stimulated animals.","date":"2021","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/33993545","citation_count":10,"is_preprint":false},{"pmid":"38770619","id":"PMC_38770619","title":"The ameliorative mechanism of 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genetiki i selektsii","url":"https://pubmed.ncbi.nlm.nih.gov/41660605","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16912,"output_tokens":1716,"usd":0.038238,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8554,"output_tokens":2413,"usd":0.051548,"stage2_stop_reason":"end_turn"},"total_usd":0.089786,"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\": 2007,\n      \"finding\": \"NDUFA7 (B14.5a) is a phosphorylated subunit of bovine heart mitochondrial complex I, as detected by mass spectrometry following nondenaturing gel electrophoretic separation and phosphopeptide enrichment with titanium dioxide.\",\n      \"method\": \"Native PAGE separation of complex I, in-gel digestion, TiO2 phosphopeptide enrichment, MS/MS\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct MS detection of phosphorylation in purified complex I, single lab, single method\",\n      \"pmids\": [\"17443843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NDUFA7 is succinylated in mouse heart mitochondria; succinylation of NDUFA7 is uniquely detected in Sirt5-knockout (but not wild-type) hearts, indicating that SIRT5 acts as a desuccinylase that removes succinyl modifications from NDUFA7.\",\n      \"method\": \"Affinity enrichment of succinylated peptides, LC-MS/MS proteomics, comparison of WT vs. Sirt5−/− mouse heart mitochondria\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MS-based PTM identification in KO vs WT, single lab, single method, no direct enzymatic reconstitution\",\n      \"pmids\": [\"26388266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NDUFA7 is a subunit of the Q-module of mitochondrial complex I; loss of NDUFA6 (a related Q-module subunit) leads to a concomitant reduction in incorporated NDUFA7 along with other Q-module subunits (NDUFAB1, NDUFA12), as shown by complexome profiling.\",\n      \"method\": \"Mass-spectrometry-based complexome profiling of patient fibroblast cell lines with bi-allelic NDUFA6 variants; lentiviral transduction rescue\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complexome profiling with rescue experiment, single lab, two orthogonal methods (complexome profiling + lentiviral complementation)\",\n      \"pmids\": [\"30245030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The NDUFA7 gene (encoding complex I subunit B14.5a) maps to human chromosome 20p13, as determined by in situ hybridization of isolated genomic clones.\",\n      \"method\": \"Screening of human cosmid and P1 libraries, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct cytogenetic mapping experiment, single lab, single method\",\n      \"pmids\": [\"9345899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NDUFA7 physically interacts with the mitochondrial micropeptide MPM; overexpression of MPM inhibits mitochondrial complex I activity, and this inhibitory effect is attenuated by siRNA-mediated knockdown of NDUFA7, placing NDUFA7 as the functional mediator of MPM's effect on complex I.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP) interaction assay, siRNA knockdown, mitochondrial complex I activity assay, NAD+/NADH ratio measurement\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional epistasis (MPM effect rescued by NDUFA7 KD), Co-IP binding, enzymatic activity assay; single lab\",\n      \"pmids\": [\"34478872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NDUFA7 depletion in zebrafish embryos causes cardiac development and functional defects, increases expression of pathological hypertrophy biomarkers (nppa/ANP, nppb/BNP), promotes mitochondrial ROS production, and activates calcineurin signalling, establishing a role for NDUFA7 in restraining pathological cardiac hypertrophy via the ROS-calcineurin axis.\",\n      \"method\": \"Morpholino/siRNA knockdown in zebrafish embryos; cardiac functional assays; ROS measurement; calcineurin signalling assessment; biomarker gene expression (nppa, nppb)\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in vivo model with defined molecular phenotype (ROS, calcineurin), single lab, multiple readouts\",\n      \"pmids\": [\"32989924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NDUFA7 complex I protein levels are reduced in renal tubular cells when miR-3960 (delivered via B-cell-derived extracellular vesicles) targets TRMT5, a mitochondrial tRNA methyltransferase; this places NDUFA7 downstream of TRMT5-dependent mitochondrial tRNA modification in maintaining complex I biogenesis.\",\n      \"method\": \"Dual-luciferase reporter assay, co-immunoprecipitation, EV blockade experiments, miR-3960 depletion in obesity mouse model\",\n      \"journal\": \"Small\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — NDUFA7 reduction is an indirect downstream readout; direct mechanistic link to NDUFA7 not experimentally interrogated beyond protein level changes\",\n      \"pmids\": [\"38958071\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NDUFA7 (B14.5a) is a structural subunit of the Q-module of mitochondrial respiratory chain complex I that is phosphorylated and succinylated (the latter regulated by the deacylase SIRT5); it physically interacts with the micropeptide MPM to modulate complex I activity and the NAD+/NADH ratio, and its loss triggers ROS overproduction and calcineurin pathway activation leading to pathological cardiac hypertrophy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NDUFA7 (B14.5a) is a structural subunit of the Q-module of mitochondrial respiratory chain complex I, where its incorporation depends on the integrity of other Q-module subunits and is reduced upon loss of NDUFA6 [#2]. The protein carries regulatory post-translational modifications: it is phosphorylated within assembled complex I [#0] and succinylated, with the modification accumulating in Sirt5-knockout heart mitochondria, identifying SIRT5 as a desuccinylase acting on NDUFA7 [#1]. Functionally, NDUFA7 mediates the inhibitory effect of the mitochondrial micropeptide MPM on complex I activity and the NAD+/NADH ratio, since MPM physically binds NDUFA7 and the inhibition is lost upon NDUFA7 knockdown [#4]. Loss of NDUFA7 in vivo causes cardiac developmental and functional defects, drives mitochondrial ROS overproduction and calcineurin signalling, and induces pathological hypertrophy biomarkers, establishing a role in restraining pathological cardiac hypertrophy [#5]. The gene maps to human chromosome 20p13 [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the genomic location of NDUFA7 provided the foundational locus assignment for the complex I subunit B14.5a.\",\n      \"evidence\": \"Library screening and FISH mapping of genomic clones\",\n      \"pmids\": [\"9345899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or structural information about the protein\", \"Gene structure and regulatory elements not characterized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Detection of NDUFA7 phosphorylation in purified complex I raised the question of regulatory post-translational control of the subunit.\",\n      \"evidence\": \"Native PAGE separation, TiO2 phosphopeptide enrichment, MS/MS of bovine heart complex I\",\n      \"pmids\": [\"17443843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Responsible kinase not identified\", \"Functional consequence of phosphorylation on complex I activity not tested\", \"Phosphosite stoichiometry unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying NDUFA7 succinylation as SIRT5-regulated connected the subunit to deacylase-dependent metabolic control of complex I.\",\n      \"evidence\": \"Succinyl-peptide affinity enrichment and LC-MS/MS comparing WT vs Sirt5-/- mouse heart mitochondria\",\n      \"pmids\": [\"26388266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct enzymatic reconstitution of SIRT5 acting on NDUFA7\", \"Effect of succinylation on complex I function not measured\", \"Modified residues' functional roles unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Assigning NDUFA7 to the Q-module and showing its co-dependence with NDUFA6 defined its structural position within complex I assembly.\",\n      \"evidence\": \"Complexome profiling of NDUFA6-variant patient fibroblasts with lentiviral rescue\",\n      \"pmids\": [\"30245030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NDUFA7-NDUFA6 contacts not mapped structurally\", \"Whether NDUFA7 loss reciprocally destabilizes other subunits not tested here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"In vivo depletion linked NDUFA7 loss to ROS overproduction, calcineurin activation, and pathological cardiac hypertrophy, giving the subunit a physiological role beyond bioenergetics.\",\n      \"evidence\": \"Morpholino/siRNA knockdown in zebrafish embryos with cardiac, ROS, and calcineurin readouts\",\n      \"pmids\": [\"32989924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between complex I deficiency and calcineurin not dissected\", \"Mammalian cardiac model not tested\", \"Whether effect is cell-autonomous to cardiomyocytes unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that NDUFA7 mediates the micropeptide MPM's inhibition of complex I identified a direct partner controlling complex I activity and NAD+/NADH balance.\",\n      \"evidence\": \"Co-IP, siRNA knockdown epistasis, complex I activity and NAD+/NADH assays\",\n      \"pmids\": [\"34478872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface and stoichiometry of MPM-NDUFA7 not defined\", \"Reciprocal validation in additional systems limited\", \"Whether MPM alters NDUFA7 PTM status unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"NDUFA7 protein levels were placed downstream of TRMT5-dependent mitochondrial tRNA modification, implicating it as a readout of complex I biogenesis under EV-microRNA control.\",\n      \"evidence\": \"Dual-luciferase reporter, Co-IP, EV blockade, miR-3960 depletion in obesity mouse model\",\n      \"pmids\": [\"38958071\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"NDUFA7 reduction is an indirect downstream readout not mechanistically interrogated\", \"No direct link between TRMT5 and NDUFA7 expression\", \"Specificity to NDUFA7 versus general complex I loss unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the phosphorylation, succinylation, and MPM-binding inputs are integrated to tune NDUFA7's contribution to complex I activity and downstream ROS/calcineurin signalling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model placing PTM sites and the MPM interface within complex I\", \"Kinase and direct enzymatic regulators not identified\", \"Causal chain from complex I dysfunction to calcineurin activation not delineated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [\"mitochondrial respiratory chain complex I (Q-module)\"],\n    \"partners\": [\"MPM\", \"NDUFA6\", \"SIRT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}