{"gene":"NDUFV2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1995,"finding":"NDUFV2 encodes the 24-kDa iron-sulfur subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase), containing one [2Fe-2S] binuclear cluster (N1a); the gene spans ~20–31.5 kb with 8 exons, maps to chromosome 18p11.2-p11.31, and a pseudogene (NDUFV2P1) resides on chromosome 19q13.3.","method":"Molecular cloning, cosmid library screening, FISH chromosomal mapping, cDNA sequencing","journal":"Genomics / Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural characterization with multiple orthogonal methods (cloning, sequencing, FISH), replicated across two independent labs in the same year","pmids":["7607668","7488192"],"is_preprint":false},{"year":1995,"finding":"The 5' flanking region of NDUFV2 lacks canonical CAAT and TATA boxes but contains three putative GC boxes, consistent with a housekeeping-type promoter architecture.","method":"DNA sequencing and promoter region analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct sequencing of the promoter region, single lab but clear structural finding","pmids":["7488192"],"is_preprint":false},{"year":2003,"finding":"A homozygous 4-bp deletion in intron 2 (IVS2+5_+8delGTAA) of NDUFV2, disrupting the consensus splice-donor site of exon 2, results in ~70% decreased NDUFV2 protein and Complex I deficiency causing early-onset hypertrophic cardiomyopathy and encephalopathy.","method":"DHPLC, sequence analysis, protein quantification in patient-derived cells","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional mutation analysis confirmed at protein and enzymatic level, replicated in subsequent family studies","pmids":["12754703"],"is_preprint":false},{"year":2007,"finding":"Transcription factor Sp1 directly activates the NDUFV2 promoter by binding to its three GC-boxes; the Sp1/DNA binding inhibitor mithramycin inhibits both Sp1 binding and NDUFV2 transcription in neuroblastoma cells.","method":"Promoter-reporter (luciferase) assay, electrophoretic mobility shift assay (EMSA), pharmacological inhibition with mithramycin","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct promoter binding demonstrated by EMSA plus functional reporter assay with mithramycin inhibition, two orthogonal methods in one study","pmids":["17786189"],"is_preprint":false},{"year":2004,"finding":"A promoter SNP in NDUFV2 (-602G>A) alters promoter activity as demonstrated by promoter assay, providing functional significance for the genetic association with bipolar disorder.","method":"Promoter reporter assay","journal":"Biological psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single functional assay demonstrating altered promoter activity","pmids":["15450783"],"is_preprint":false},{"year":2011,"finding":"The mitochondrial targeting sequence (MTS) of NDUFV2 resides in the N-terminal ~22 residues; the cleavage site is around amino acid 32. Mitochondrial import requires maintenance of net positive charge and amphiphilic structure through the balance of basic and hydrophobic residues. The disease mutation (IVS2+5_+8delGTAA), which deletes residues 19–40, significantly impairs mitochondrial targeting and localization.","method":"Confocal microscopy of c-myc-tagged deletion/point-mutant constructs, GFP-fusion constructs, site-directed mutagenesis in human cells","journal":"Journal of biomedical science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with mutagenesis and multiple deletion constructs validated by imaging, single lab but multiple orthogonal approaches","pmids":["21548921"],"is_preprint":false},{"year":2017,"finding":"Adenosine A2 receptor agonist NECA activates mitochondrial Src tyrosine kinase, which phosphorylates Tyr118 of NDUFV2 and thereby inhibits Complex I activity and reduces mitochondrial superoxide generation upon reperfusion. Mutation Y118F in NDUFV2 abolished NECA-mediated Complex I inhibition, identifying Tyr118 as a negative regulatory site of Complex I.","method":"LC-MS phosphoproteomics, site-directed mutagenesis (Y118F), Complex I activity assay, mitochondrial ROS measurement, transfection in H9c2 cells, isolated perfused rat hearts","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — LC-MS identification of phosphorylation site confirmed by mutagenesis with functional readout (Complex I activity), multiple orthogonal methods in one study","pmids":["28219781"],"is_preprint":false},{"year":2021,"finding":"Ndufv2 regulates mitochondrial supercomplex assembly and elevates mitochondrial reactive oxygen species (ROS) production; overexpression of Ndufv2 in adipose tissue increases mitochondrial biogenesis through an ROS-dependent signaling mechanism and controls expression of at least 89 mitochondrial genes in a sex- and tissue-specific manner.","method":"Genetic locus mapping in inbred mouse strains, Ndufv2 overexpression studies, mitochondrial supercomplex assembly assays, ROS measurement, mitochondrial biogenesis assays","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic locus mapping plus functional overexpression with mechanistic readouts (supercomplex assembly, ROS, biogenesis), replicated in mice and humans","pmids":["34697471"],"is_preprint":false},{"year":2023,"finding":"PHB2 (Prohibitin 2) physically interacts with NDUFV2 and promotes its protein stability; PHB2 deficiency reduces NDUFV2 protein levels and impairs Complex I activity and mitochondrial bioenergetics in DOX-challenged cardiomyocytes.","method":"Co-immunoprecipitation, pulldown assay, proteomic profiling, cardiac-specific conditional PHB2 knockout mouse model, in vivo/in vitro functional assays","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and pulldown confirming interaction, validated in genetic KO model with functional Complex I readout, multiple orthogonal methods","pmids":["37451140"],"is_preprint":false},{"year":2018,"finding":"The NDUFV2 pseudogene (NDUFV2P1) expression is inversely correlated with NDUFV2 protein levels and Complex I-driven cellular respiration in schizophrenia-derived cells, suggesting a post-transcriptional regulatory role where NDUFV2P1 negatively controls NDUFV2 protein without changing mRNA levels.","method":"Cell fractionation, protein quantification, Complex I activity (oxygen consumption), correlation analysis in schizophrenia-derived cell lines and postmortem brain","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — correlative inverse relationship in patient-derived cells and postmortem brain, no direct manipulation experiment in this paper; mechanism not yet fully established","pmids":["30531937"],"is_preprint":false},{"year":2026,"finding":"NDUFV2P1 (pseudogene) attenuates mRNA transport of NDUFV2 by competing for NXF1 (nuclear export factor 1) binding and altering RNA-binding protein (RBP) interactions, thereby reducing NDUFV2 nuclear export and protein levels; overexpression of NDUFV2P1 in control lymphoblastoid cells mimics the schizophrenia state by reducing NDUFV2 mRNA export and protein.","method":"Subcellular fractionation, RNA immunoprecipitation (NXF1 binding), NDUFV2P1 overexpression in control cell lines, RBP interactome analysis","journal":"Schizophrenia (Heidelberg)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct overexpression experiment recapitulating phenotype, NXF1 binding assay as mechanistic evidence, single lab with multiple orthogonal methods but requiring further validation per authors","pmids":["42259816"],"is_preprint":false},{"year":2026,"finding":"SKQ1 (a mitochondria-targeted plastoquinone antioxidant) directly binds NDUFV2 and induces Complex I dysfunction, leading to a burst of mitochondrial ROS and tumor cell apoptosis; NDUFV2 knockout abolished SKQ1's pro-apoptotic effects.","method":"Direct binding assay, NDUFV2 knockout cell lines, ROS measurement, apoptosis assays, xenograft models","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO confirmation of mechanism with functional ROS and apoptosis readouts, single lab study","pmids":["42119952"],"is_preprint":false},{"year":2025,"finding":"NDUFV2 mediates hypoxia-derived tumor exosome-induced M2 macrophage polarization by increasing mitochondrial OXPHOS, ATP levels, and mitochondrial membrane potential, thereby suppressing macrophage ferroptosis; NDUFV2 knockdown in macrophages abrogated exosome-induced bystander radioresistance.","method":"NDUFV2 knockdown in macrophages, exosome co-culture assays, mitochondrial function measurement (OXPHOS, ATP, ΔΨm), in vivo xenograft models with macrophage depletion","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi-based loss-of-function with defined functional readouts and in vivo validation, single lab","pmids":["41419454"],"is_preprint":false},{"year":2022,"finding":"NDUFV2 gene silencing (shRNA) inhibits proliferation of drug-resistant cancer cell lines MCF-7/ADR and SMMC-7721/ADR with inhibition rates of ~67–74%, establishing NDUFV2 as required for growth of these cells.","method":"shRNA-mediated gene silencing, cell proliferation assay","journal":"Journal of genetic engineering & biotechnology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (shRNA knockdown + proliferation assay), no mechanistic pathway defined","pmids":["35471675"],"is_preprint":false}],"current_model":"NDUFV2 encodes the 24-kDa [2Fe-2S] iron-sulfur subunit (N1a cluster) of the N-module of mitochondrial Complex I; its N-terminal ~22-residue mitochondrial targeting sequence (cleaved near residue 32) imports it into the mitochondrial matrix, where it is stabilized by PHB2 interaction. Complex I activity is negatively regulated by Src-dependent phosphorylation of NDUFV2 Tyr118, and NDUFV2 controls supercomplex assembly and mitochondrial ROS production — which in turn drives mitochondrial biogenesis. Its promoter is activated by transcription factor Sp1 via three GC-boxes, and its pseudogene NDUFV2P1 negatively regulates NDUFV2 mRNA nuclear export by competing for NXF1 and RNA-binding proteins. Loss-of-function mutations cause Complex I deficiency manifesting as cardiomyopathy, Leigh syndrome, or leukoencephalopathy depending on genotype."},"narrative":{"mechanistic_narrative":"NDUFV2 encodes the 24-kDa iron-sulfur subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase), carrying a single [2Fe-2S] (N1a) cluster and contributing to the catalytic core of the enzyme [PMID:7607668, PMID:7488192]. The protein is imported into the mitochondrial matrix via an N-terminal targeting sequence (cleaved near residue 32) whose net positive charge and amphiphilic character are required for correct localization [PMID:21548921], and its mature stability depends on physical interaction with PHB2 (Prohibitin 2) [PMID:37451140]. Beyond providing structural and catalytic function, NDUFV2 governs higher-order respiratory chain organization and mitochondrial ROS output: it regulates supercomplex assembly and, through ROS-dependent signaling, drives mitochondrial biogenesis [PMID:34697471]. Complex I activity through NDUFV2 is acutely tunable by post-translational control, as Src-mediated phosphorylation of Tyr118 inhibits the enzyme and lowers mitochondrial superoxide generation [PMID:28219781]. NDUFV2 transcription is directed by a housekeeping-type GC-box promoter activated by Sp1 [PMID:7488192, PMID:17786189], and its protein output is further constrained post-transcriptionally by the pseudogene NDUFV2P1, which limits NDUFV2 mRNA nuclear export by competing for NXF1 binding [PMID:42259816]. Loss-of-function mutation — a splice-disrupting intron 2 deletion that reduces protein and impairs import — causes Complex I deficiency presenting as hypertrophic cardiomyopathy and encephalopathy [PMID:12754703, PMID:21548921]. Through its control of OXPHOS capacity and ROS, NDUFV2 modulates cell fate and survival in cancer contexts, including drug-resistant tumor cell proliferation and macrophage polarization [PMID:42119952, PMID:41419454].","teleology":[{"year":1995,"claim":"Establishing the molecular identity of NDUFV2 defined it as the [2Fe-2S]-bearing 24-kDa subunit of Complex I and located the gene and its pseudogene in the genome.","evidence":"Molecular cloning, cDNA sequencing, and FISH chromosomal mapping","pmids":["7607668","7488192"],"confidence":"High","gaps":["Does not localize the subunit within the Complex I module architecture","Functional role of the N1a cluster in electron transfer not addressed here"]},{"year":1995,"claim":"Characterizing the promoter as TATA/CAAT-less with three GC boxes framed NDUFV2 as a housekeeping gene and predicted GC-box-dependent transcriptional control.","evidence":"DNA sequencing and promoter region analysis","pmids":["7488192"],"confidence":"Medium","gaps":["Does not identify the transcription factors binding the GC boxes","No functional reporter validation in this study"]},{"year":2003,"claim":"Identifying a homozygous splice-disrupting intron 2 deletion linked NDUFV2 loss-of-function directly to Complex I deficiency disease.","evidence":"DHPLC, sequencing, and protein quantification in patient-derived cells","pmids":["12754703"],"confidence":"High","gaps":["Mechanism by which reduced protein impairs assembly not resolved here","Genotype-phenotype basis for variable presentation unaddressed"]},{"year":2004,"claim":"A functional promoter SNP showed that NDUFV2 transcriptional output is genetically variable, providing a mechanistic anchor for disease association.","evidence":"Promoter reporter assay","pmids":["15450783"],"confidence":"Medium","gaps":["Single functional assay, no endogenous expression validation","Causal contribution to phenotype not established"]},{"year":2007,"claim":"Demonstrating that Sp1 binds the GC boxes and activates the promoter identified the transcription factor controlling NDUFV2 expression.","evidence":"Luciferase reporter, EMSA, and mithramycin inhibition in neuroblastoma cells","pmids":["17786189"],"confidence":"High","gaps":["Other regulators acting on the promoter not excluded","Cell-type specificity of Sp1 dependence not characterized"]},{"year":2011,"claim":"Mapping the mitochondrial targeting sequence explained how NDUFV2 reaches the matrix and why the disease deletion is pathogenic at the import level.","evidence":"Confocal imaging of tagged deletion/point mutants and site-directed mutagenesis in human cells","pmids":["21548921"],"confidence":"High","gaps":["Import machinery (TOM/TIM) interactions not directly mapped","Processing protease cleaving near residue 32 not identified"]},{"year":2017,"claim":"Identifying Src-dependent Tyr118 phosphorylation established a post-translational switch that negatively regulates Complex I and tunes mitochondrial ROS.","evidence":"LC-MS phosphoproteomics, Y118F mutagenesis, Complex I activity and ROS assays in H9c2 cells and perfused rat hearts","pmids":["28219781"],"confidence":"High","gaps":["Structural basis for how Tyr118 phosphorylation inhibits catalysis not defined","Counteracting phosphatase not identified"]},{"year":2018,"claim":"Correlating pseudogene expression inversely with NDUFV2 protein introduced post-transcriptional regulation by NDUFV2P1.","evidence":"Cell fractionation, protein quantification, and respiration measurement in schizophrenia-derived cells and postmortem brain","pmids":["30531937"],"confidence":"Medium","gaps":["Correlative only, no direct manipulation in this study","Molecular mechanism of repression not yet defined"]},{"year":2021,"claim":"Genetic mapping and overexpression revealed NDUFV2 as a controller of supercomplex assembly, ROS, and downstream mitochondrial biogenesis.","evidence":"Inbred-strain locus mapping, Ndufv2 overexpression, supercomplex assembly, ROS, and biogenesis assays in mice and humans","pmids":["34697471"],"confidence":"High","gaps":["Mechanism linking ROS signal to biogenesis transcriptional program not detailed","Basis for sex- and tissue-specific gene regulation unresolved"]},{"year":2023,"claim":"Identifying PHB2 as a physical partner that stabilizes NDUFV2 connected protein stability to Complex I integrity in stressed cardiomyocytes.","evidence":"Reciprocal Co-IP, pulldown, proteomics, and cardiac-specific PHB2 knockout mouse with functional assays","pmids":["37451140"],"confidence":"High","gaps":["Whether PHB2 acts as a chaperone or assembly factor not distinguished","Stoichiometry and binding interface not mapped"]},{"year":2025,"claim":"Loss-of-function in macrophages showed NDUFV2-driven OXPHOS suppresses ferroptosis and confers exosome-induced radioresistance, extending its role to immune cell metabolism.","evidence":"NDUFV2 knockdown, exosome co-culture, mitochondrial function readouts, and in vivo macrophage-depletion xenografts","pmids":["41419454"],"confidence":"Medium","gaps":["Single lab; direct link between Complex I activity and ferroptosis pathway not dissected","Whether NDUFV2 acts upstream or downstream of polarization signals unclear"]},{"year":2026,"claim":"Defining NXF1 competition by NDUFV2P1 provided the molecular mechanism for pseudogene-mediated suppression of NDUFV2 mRNA export.","evidence":"Subcellular fractionation, NXF1 RNA immunoprecipitation, NDUFV2P1 overexpression, and RBP interactome analysis","pmids":["42259816"],"confidence":"Medium","gaps":["Single lab requiring further validation per authors","Identity of the cooperating RBPs not fully resolved"]},{"year":2026,"claim":"Showing that SKQ1 binds NDUFV2 to trigger Complex I dysfunction and apoptosis established NDUFV2 as a druggable node for ROS-dependent tumor cell death.","evidence":"Direct binding assay, NDUFV2 knockout cells, ROS and apoptosis assays, and xenograft models","pmids":["42119952"],"confidence":"Medium","gaps":["Binding site on NDUFV2 not mapped","Selectivity over other Complex I subunits not established"]},{"year":null,"claim":"How NDUFV2-dependent ROS signals are transduced into transcriptional programs for biogenesis and cell fate, and the structural basis of its regulatory phosphorylation and small-molecule binding, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of NDUFV2 within human Complex I in the corpus","Downstream effectors of ROS signaling unidentified","Integration of transcriptional (Sp1), post-transcriptional (NDUFV2P1), and post-translational (Tyr118) layers not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,6,7]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,5,8]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,7]}],"complexes":["Mitochondrial Complex I (NADH:ubiquinone oxidoreductase)","Respiratory supercomplex"],"partners":["PHB2","SRC","SP1","NXF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P19404","full_name":"NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial","aliases":["NADH-ubiquinone oxidoreductase 24 kDa subunit"],"length_aa":249,"mass_kda":27.4,"function":"Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor (Probable). Parts of the peripheral arm of the enzyme, where the electrons from NADH are accepted by flavin mononucleotide (FMN) and then passed along a chain of iron-sulfur clusters by electron tunnelling to the final acceptor ubiquinone (Probable). Contains one iron-sulfur cluster (Probable)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/P19404/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NDUFV2","classification":"Not Classified","n_dependent_lines":325,"n_total_lines":1208,"dependency_fraction":0.26903973509933776},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CBX1","stoichiometry":0.2},{"gene":"NVL","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NDUFV2","total_profiled":1310},"omim":[{"mim_id":"618229","title":"MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 7; MC1DN7","url":"https://www.omim.org/entry/618229"},{"mim_id":"617228","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 31; COXPD31","url":"https://www.omim.org/entry/617228"},{"mim_id":"603846","title":"NADH-UBIQUINONE OXIDOREDUCTASE Fe-S PROTEIN 3; NDUFS3","url":"https://www.omim.org/entry/603846"},{"mim_id":"602241","title":"MITOCHONDRIAL INTERMEDIATE PEPTIDASE; MIPEP","url":"https://www.omim.org/entry/602241"},{"mim_id":"602184","title":"NADH-UBIQUINONE OXIDOREDUCTASE FLAVOPROTEIN 3; NDUFV3","url":"https://www.omim.org/entry/602184"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NDUFV2"},"hgnc":{"alias_symbol":["CI-24k"],"prev_symbol":[]},"alphafold":{"accession":"P19404","domains":[{"cath_id":"1.10.10.1590","chopping":"33-125","consensus_level":"medium","plddt":92.968,"start":33,"end":125},{"cath_id":"3.40.30.10","chopping":"131-219","consensus_level":"high","plddt":95.767,"start":131,"end":219}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P19404","model_url":"https://alphafold.ebi.ac.uk/files/AF-P19404-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P19404-F1-predicted_aligned_error_v6.png","plddt_mean":86.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NDUFV2","jax_strain_url":"https://www.jax.org/strain/search?query=NDUFV2"},"sequence":{"accession":"P19404","fasta_url":"https://rest.uniprot.org/uniprotkb/P19404.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P19404/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P19404"}},"corpus_meta":[{"pmid":"12754703","id":"PMC_12754703","title":"Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy.","date":"2003","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/12754703","citation_count":133,"is_preprint":false},{"pmid":"12815743","id":"PMC_12815743","title":"Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with bipolar disorder.","date":"2003","source":"American journal of medical genetics. 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biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/35471675","citation_count":3,"is_preprint":false},{"pmid":"41419454","id":"PMC_41419454","title":"Hypoxic tumor exosomes suppress macrophage inflammation and ferroptosis via NDUFV2 to enhance bystander tumor radioresistance.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41419454","citation_count":3,"is_preprint":false},{"pmid":"36309697","id":"PMC_36309697","title":"Association between single-nucleotide polymorphism rs145497186 related to NDUFV2 and lumbar disc degeneration: a pilot case-control study.","date":"2022","source":"Journal of orthopaedic surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/36309697","citation_count":1,"is_preprint":false},{"pmid":"39634239","id":"PMC_39634239","title":"A Novel NDUFV2 Variant in an Asymptomatic Adolescent Girl with Progressive Cavitating Leukoencephalopathy.","date":"2024","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/39634239","citation_count":0,"is_preprint":false},{"pmid":"42040813","id":"PMC_42040813","title":"Expression Study of NDUFS1, NDUFV1, and NDUFV2 in Schizophrenia and Paranoid Personality Disorder : Role of Mitochondrial Complex I in SCZ and PPD.","date":"2022","source":"Galen medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/42040813","citation_count":0,"is_preprint":false},{"pmid":"42119952","id":"PMC_42119952","title":"SKQ1 promotes tumor cell apoptosis by directly interacting with NDUFV2 and inducing superoxide production.","date":"2026","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42119952","citation_count":0,"is_preprint":false},{"pmid":"42259816","id":"PMC_42259816","title":"A new mechanism underlying mitochondrial dysfunction in schizophrenia - attenuated mRNA transport of the complex I subunit NDUFV2 by its pseudogene NDUFV2P1.","date":"2026","source":"Schizophrenia (Heidelberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/42259816","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.07.647592","title":"AMPK is dispensable for physiological podocyte and glomerular functions but prevents glomerular fibrosis in experimental diabetes","date":"2025-04-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.07.647592","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18229,"output_tokens":3460,"usd":0.053294,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11139,"output_tokens":3872,"usd":0.076247,"stage2_stop_reason":"end_turn"},"total_usd":0.129541,"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\": 1995,\n      \"finding\": \"NDUFV2 encodes the 24-kDa iron-sulfur subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase), containing one [2Fe-2S] binuclear cluster (N1a); the gene spans ~20–31.5 kb with 8 exons, maps to chromosome 18p11.2-p11.31, and a pseudogene (NDUFV2P1) resides on chromosome 19q13.3.\",\n      \"method\": \"Molecular cloning, cosmid library screening, FISH chromosomal mapping, cDNA sequencing\",\n      \"journal\": \"Genomics / Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural characterization with multiple orthogonal methods (cloning, sequencing, FISH), replicated across two independent labs in the same year\",\n      \"pmids\": [\"7607668\", \"7488192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The 5' flanking region of NDUFV2 lacks canonical CAAT and TATA boxes but contains three putative GC boxes, consistent with a housekeeping-type promoter architecture.\",\n      \"method\": \"DNA sequencing and promoter region analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct sequencing of the promoter region, single lab but clear structural finding\",\n      \"pmids\": [\"7488192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A homozygous 4-bp deletion in intron 2 (IVS2+5_+8delGTAA) of NDUFV2, disrupting the consensus splice-donor site of exon 2, results in ~70% decreased NDUFV2 protein and Complex I deficiency causing early-onset hypertrophic cardiomyopathy and encephalopathy.\",\n      \"method\": \"DHPLC, sequence analysis, protein quantification in patient-derived cells\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional mutation analysis confirmed at protein and enzymatic level, replicated in subsequent family studies\",\n      \"pmids\": [\"12754703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Transcription factor Sp1 directly activates the NDUFV2 promoter by binding to its three GC-boxes; the Sp1/DNA binding inhibitor mithramycin inhibits both Sp1 binding and NDUFV2 transcription in neuroblastoma cells.\",\n      \"method\": \"Promoter-reporter (luciferase) assay, electrophoretic mobility shift assay (EMSA), pharmacological inhibition with mithramycin\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct promoter binding demonstrated by EMSA plus functional reporter assay with mithramycin inhibition, two orthogonal methods in one study\",\n      \"pmids\": [\"17786189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A promoter SNP in NDUFV2 (-602G>A) alters promoter activity as demonstrated by promoter assay, providing functional significance for the genetic association with bipolar disorder.\",\n      \"method\": \"Promoter reporter assay\",\n      \"journal\": \"Biological psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single functional assay demonstrating altered promoter activity\",\n      \"pmids\": [\"15450783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The mitochondrial targeting sequence (MTS) of NDUFV2 resides in the N-terminal ~22 residues; the cleavage site is around amino acid 32. Mitochondrial import requires maintenance of net positive charge and amphiphilic structure through the balance of basic and hydrophobic residues. The disease mutation (IVS2+5_+8delGTAA), which deletes residues 19–40, significantly impairs mitochondrial targeting and localization.\",\n      \"method\": \"Confocal microscopy of c-myc-tagged deletion/point-mutant constructs, GFP-fusion constructs, site-directed mutagenesis in human cells\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with mutagenesis and multiple deletion constructs validated by imaging, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"21548921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Adenosine A2 receptor agonist NECA activates mitochondrial Src tyrosine kinase, which phosphorylates Tyr118 of NDUFV2 and thereby inhibits Complex I activity and reduces mitochondrial superoxide generation upon reperfusion. Mutation Y118F in NDUFV2 abolished NECA-mediated Complex I inhibition, identifying Tyr118 as a negative regulatory site of Complex I.\",\n      \"method\": \"LC-MS phosphoproteomics, site-directed mutagenesis (Y118F), Complex I activity assay, mitochondrial ROS measurement, transfection in H9c2 cells, isolated perfused rat hearts\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — LC-MS identification of phosphorylation site confirmed by mutagenesis with functional readout (Complex I activity), multiple orthogonal methods in one study\",\n      \"pmids\": [\"28219781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ndufv2 regulates mitochondrial supercomplex assembly and elevates mitochondrial reactive oxygen species (ROS) production; overexpression of Ndufv2 in adipose tissue increases mitochondrial biogenesis through an ROS-dependent signaling mechanism and controls expression of at least 89 mitochondrial genes in a sex- and tissue-specific manner.\",\n      \"method\": \"Genetic locus mapping in inbred mouse strains, Ndufv2 overexpression studies, mitochondrial supercomplex assembly assays, ROS measurement, mitochondrial biogenesis assays\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic locus mapping plus functional overexpression with mechanistic readouts (supercomplex assembly, ROS, biogenesis), replicated in mice and humans\",\n      \"pmids\": [\"34697471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHB2 (Prohibitin 2) physically interacts with NDUFV2 and promotes its protein stability; PHB2 deficiency reduces NDUFV2 protein levels and impairs Complex I activity and mitochondrial bioenergetics in DOX-challenged cardiomyocytes.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assay, proteomic profiling, cardiac-specific conditional PHB2 knockout mouse model, in vivo/in vitro functional assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and pulldown confirming interaction, validated in genetic KO model with functional Complex I readout, multiple orthogonal methods\",\n      \"pmids\": [\"37451140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The NDUFV2 pseudogene (NDUFV2P1) expression is inversely correlated with NDUFV2 protein levels and Complex I-driven cellular respiration in schizophrenia-derived cells, suggesting a post-transcriptional regulatory role where NDUFV2P1 negatively controls NDUFV2 protein without changing mRNA levels.\",\n      \"method\": \"Cell fractionation, protein quantification, Complex I activity (oxygen consumption), correlation analysis in schizophrenia-derived cell lines and postmortem brain\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — correlative inverse relationship in patient-derived cells and postmortem brain, no direct manipulation experiment in this paper; mechanism not yet fully established\",\n      \"pmids\": [\"30531937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NDUFV2P1 (pseudogene) attenuates mRNA transport of NDUFV2 by competing for NXF1 (nuclear export factor 1) binding and altering RNA-binding protein (RBP) interactions, thereby reducing NDUFV2 nuclear export and protein levels; overexpression of NDUFV2P1 in control lymphoblastoid cells mimics the schizophrenia state by reducing NDUFV2 mRNA export and protein.\",\n      \"method\": \"Subcellular fractionation, RNA immunoprecipitation (NXF1 binding), NDUFV2P1 overexpression in control cell lines, RBP interactome analysis\",\n      \"journal\": \"Schizophrenia (Heidelberg)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct overexpression experiment recapitulating phenotype, NXF1 binding assay as mechanistic evidence, single lab with multiple orthogonal methods but requiring further validation per authors\",\n      \"pmids\": [\"42259816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SKQ1 (a mitochondria-targeted plastoquinone antioxidant) directly binds NDUFV2 and induces Complex I dysfunction, leading to a burst of mitochondrial ROS and tumor cell apoptosis; NDUFV2 knockout abolished SKQ1's pro-apoptotic effects.\",\n      \"method\": \"Direct binding assay, NDUFV2 knockout cell lines, ROS measurement, apoptosis assays, xenograft models\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO confirmation of mechanism with functional ROS and apoptosis readouts, single lab study\",\n      \"pmids\": [\"42119952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NDUFV2 mediates hypoxia-derived tumor exosome-induced M2 macrophage polarization by increasing mitochondrial OXPHOS, ATP levels, and mitochondrial membrane potential, thereby suppressing macrophage ferroptosis; NDUFV2 knockdown in macrophages abrogated exosome-induced bystander radioresistance.\",\n      \"method\": \"NDUFV2 knockdown in macrophages, exosome co-culture assays, mitochondrial function measurement (OXPHOS, ATP, ΔΨm), in vivo xenograft models with macrophage depletion\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi-based loss-of-function with defined functional readouts and in vivo validation, single lab\",\n      \"pmids\": [\"41419454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NDUFV2 gene silencing (shRNA) inhibits proliferation of drug-resistant cancer cell lines MCF-7/ADR and SMMC-7721/ADR with inhibition rates of ~67–74%, establishing NDUFV2 as required for growth of these cells.\",\n      \"method\": \"shRNA-mediated gene silencing, cell proliferation assay\",\n      \"journal\": \"Journal of genetic engineering & biotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (shRNA knockdown + proliferation assay), no mechanistic pathway defined\",\n      \"pmids\": [\"35471675\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NDUFV2 encodes the 24-kDa [2Fe-2S] iron-sulfur subunit (N1a cluster) of the N-module of mitochondrial Complex I; its N-terminal ~22-residue mitochondrial targeting sequence (cleaved near residue 32) imports it into the mitochondrial matrix, where it is stabilized by PHB2 interaction. Complex I activity is negatively regulated by Src-dependent phosphorylation of NDUFV2 Tyr118, and NDUFV2 controls supercomplex assembly and mitochondrial ROS production — which in turn drives mitochondrial biogenesis. Its promoter is activated by transcription factor Sp1 via three GC-boxes, and its pseudogene NDUFV2P1 negatively regulates NDUFV2 mRNA nuclear export by competing for NXF1 and RNA-binding proteins. Loss-of-function mutations cause Complex I deficiency manifesting as cardiomyopathy, Leigh syndrome, or leukoencephalopathy depending on genotype.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NDUFV2 encodes the 24-kDa iron-sulfur subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase), carrying a single [2Fe-2S] (N1a) cluster and contributing to the catalytic core of the enzyme [#0]. The protein is imported into the mitochondrial matrix via an N-terminal targeting sequence (cleaved near residue 32) whose net positive charge and amphiphilic character are required for correct localization [#5], and its mature stability depends on physical interaction with PHB2 (Prohibitin 2) [#8]. Beyond providing structural and catalytic function, NDUFV2 governs higher-order respiratory chain organization and mitochondrial ROS output: it regulates supercomplex assembly and, through ROS-dependent signaling, drives mitochondrial biogenesis [#7]. Complex I activity through NDUFV2 is acutely tunable by post-translational control, as Src-mediated phosphorylation of Tyr118 inhibits the enzyme and lowers mitochondrial superoxide generation [#6]. NDUFV2 transcription is directed by a housekeeping-type GC-box promoter activated by Sp1 [#1, #3], and its protein output is further constrained post-transcriptionally by the pseudogene NDUFV2P1, which limits NDUFV2 mRNA nuclear export by competing for NXF1 binding [#10]. Loss-of-function mutation — a splice-disrupting intron 2 deletion that reduces protein and impairs import — causes Complex I deficiency presenting as hypertrophic cardiomyopathy and encephalopathy [#2, #5]. Through its control of OXPHOS capacity and ROS, NDUFV2 modulates cell fate and survival in cancer contexts, including drug-resistant tumor cell proliferation and macrophage polarization [#11, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing the molecular identity of NDUFV2 defined it as the [2Fe-2S]-bearing 24-kDa subunit of Complex I and located the gene and its pseudogene in the genome.\",\n      \"evidence\": \"Molecular cloning, cDNA sequencing, and FISH chromosomal mapping\",\n      \"pmids\": [\"7607668\", \"7488192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not localize the subunit within the Complex I module architecture\", \"Functional role of the N1a cluster in electron transfer not addressed here\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Characterizing the promoter as TATA/CAAT-less with three GC boxes framed NDUFV2 as a housekeeping gene and predicted GC-box-dependent transcriptional control.\",\n      \"evidence\": \"DNA sequencing and promoter region analysis\",\n      \"pmids\": [\"7488192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the transcription factors binding the GC boxes\", \"No functional reporter validation in this study\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying a homozygous splice-disrupting intron 2 deletion linked NDUFV2 loss-of-function directly to Complex I deficiency disease.\",\n      \"evidence\": \"DHPLC, sequencing, and protein quantification in patient-derived cells\",\n      \"pmids\": [\"12754703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which reduced protein impairs assembly not resolved here\", \"Genotype-phenotype basis for variable presentation unaddressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"A functional promoter SNP showed that NDUFV2 transcriptional output is genetically variable, providing a mechanistic anchor for disease association.\",\n      \"evidence\": \"Promoter reporter assay\",\n      \"pmids\": [\"15450783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single functional assay, no endogenous expression validation\", \"Causal contribution to phenotype not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that Sp1 binds the GC boxes and activates the promoter identified the transcription factor controlling NDUFV2 expression.\",\n      \"evidence\": \"Luciferase reporter, EMSA, and mithramycin inhibition in neuroblastoma cells\",\n      \"pmids\": [\"17786189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other regulators acting on the promoter not excluded\", \"Cell-type specificity of Sp1 dependence not characterized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapping the mitochondrial targeting sequence explained how NDUFV2 reaches the matrix and why the disease deletion is pathogenic at the import level.\",\n      \"evidence\": \"Confocal imaging of tagged deletion/point mutants and site-directed mutagenesis in human cells\",\n      \"pmids\": [\"21548921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Import machinery (TOM/TIM) interactions not directly mapped\", \"Processing protease cleaving near residue 32 not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying Src-dependent Tyr118 phosphorylation established a post-translational switch that negatively regulates Complex I and tunes mitochondrial ROS.\",\n      \"evidence\": \"LC-MS phosphoproteomics, Y118F mutagenesis, Complex I activity and ROS assays in H9c2 cells and perfused rat hearts\",\n      \"pmids\": [\"28219781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how Tyr118 phosphorylation inhibits catalysis not defined\", \"Counteracting phosphatase not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Correlating pseudogene expression inversely with NDUFV2 protein introduced post-transcriptional regulation by NDUFV2P1.\",\n      \"evidence\": \"Cell fractionation, protein quantification, and respiration measurement in schizophrenia-derived cells and postmortem brain\",\n      \"pmids\": [\"30531937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative only, no direct manipulation in this study\", \"Molecular mechanism of repression not yet defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic mapping and overexpression revealed NDUFV2 as a controller of supercomplex assembly, ROS, and downstream mitochondrial biogenesis.\",\n      \"evidence\": \"Inbred-strain locus mapping, Ndufv2 overexpression, supercomplex assembly, ROS, and biogenesis assays in mice and humans\",\n      \"pmids\": [\"34697471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking ROS signal to biogenesis transcriptional program not detailed\", \"Basis for sex- and tissue-specific gene regulation unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying PHB2 as a physical partner that stabilizes NDUFV2 connected protein stability to Complex I integrity in stressed cardiomyocytes.\",\n      \"evidence\": \"Reciprocal Co-IP, pulldown, proteomics, and cardiac-specific PHB2 knockout mouse with functional assays\",\n      \"pmids\": [\"37451140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PHB2 acts as a chaperone or assembly factor not distinguished\", \"Stoichiometry and binding interface not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Loss-of-function in macrophages showed NDUFV2-driven OXPHOS suppresses ferroptosis and confers exosome-induced radioresistance, extending its role to immune cell metabolism.\",\n      \"evidence\": \"NDUFV2 knockdown, exosome co-culture, mitochondrial function readouts, and in vivo macrophage-depletion xenografts\",\n      \"pmids\": [\"41419454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; direct link between Complex I activity and ferroptosis pathway not dissected\", \"Whether NDUFV2 acts upstream or downstream of polarization signals unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defining NXF1 competition by NDUFV2P1 provided the molecular mechanism for pseudogene-mediated suppression of NDUFV2 mRNA export.\",\n      \"evidence\": \"Subcellular fractionation, NXF1 RNA immunoprecipitation, NDUFV2P1 overexpression, and RBP interactome analysis\",\n      \"pmids\": [\"42259816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab requiring further validation per authors\", \"Identity of the cooperating RBPs not fully resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showing that SKQ1 binds NDUFV2 to trigger Complex I dysfunction and apoptosis established NDUFV2 as a druggable node for ROS-dependent tumor cell death.\",\n      \"evidence\": \"Direct binding assay, NDUFV2 knockout cells, ROS and apoptosis assays, and xenograft models\",\n      \"pmids\": [\"42119952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site on NDUFV2 not mapped\", \"Selectivity over other Complex I subunits not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NDUFV2-dependent ROS signals are transduced into transcriptional programs for biogenesis and cell fate, and the structural basis of its regulatory phosphorylation and small-molecule binding, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of NDUFV2 within human Complex I in the corpus\", \"Downstream effectors of ROS signaling unidentified\", \"Integration of transcriptional (Sp1), post-transcriptional (NDUFV2P1), and post-translational (Tyr118) layers not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": []}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 5, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\"Mitochondrial Complex I (NADH:ubiquinone oxidoreductase)\", \"Respiratory supercomplex\"],\n    \"partners\": [\"PHB2\", \"SRC\", \"SP1\", \"NXF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}