{"gene":"MT-ND2","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2006,"finding":"A missense mutation (T4681C) in mitochondrial ND2 causing L71P substitution disrupts complex I assembly, leading to accumulation of specific assembly intermediates as shown by 2D blue native/SDS-PAGE, demonstrating ND2 is required for proper complex I assembly pathway.","method":"2D-BN-SDS-PAGE, transmitochondrial cybrid clones, biochemical complex I activity assay","journal":"Molecular genetics and metabolism","confidence":"High","confidence_rationale":"Tier 2 — cybrid clones confirm mitochondrial genetic origin; 2D-BN-PAGE directly visualizes assembly intermediates; multiple orthogonal methods","pmids":["16996290"],"is_preprint":false},{"year":2006,"finding":"Nuclear-mitochondrial interaction involving mt-Nd2 alleles controls mitochondrial reactive oxygen species production: ALR.mt(NOD) conplastic mice (NOD mtDNA on ALR nuclear background) produced significantly more ROS with complex I or complex II substrates compared to parental strains, establishing mt-Nd2 as a critical regulator of mitochondrial ROS output.","method":"Reciprocal conplastic mouse strains, mitochondrial respiration assay, ROS measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal conplastic design isolates mitochondrial genome contribution; multiple substrate conditions tested; strong mechanistic interpretation","pmids":["17189252"],"is_preprint":false},{"year":2010,"finding":"ND2 subunit is directly labeled by photoaffinity analogue of asimicin ([3H]BPA), a potent complex I inhibitor, identifying ND2 as part of the inhibitor/quinone-binding region of complex I; cross-linking was blocked by rotenone.","method":"Photoaffinity labeling with [3H]benzophenone-asimicin, 3D separation by blue-native/doubled SDS-PAGE","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — direct photoaffinity crosslinking in vitro with competition control (rotenone blockade); identifies ND2 at inhibitor/quinone binding site","pmids":["20074573"],"is_preprint":false},{"year":2017,"finding":"ND2 serves as a mitochondrially encoded adaptor protein that anchors Src kinase within the NMDA receptor complex via interaction with the transmembrane domain of GluN1; this interaction is enabled by the evolutionary loss of three helices in bilaterian ND2. Blocking this interaction with an ND2 fragment prevents Src-mediated upregulation of NMDAR currents in neurons.","method":"Homology modeling, computational docking, experimental validation with ND2 fragment peptide, electrophysiology in neurons","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — structural modeling validated experimentally; functional readout (NMDAR currents) confirmed; mechanistic peptide blocking experiment","pmids":["28508887"],"is_preprint":false},{"year":2019,"finding":"miR-762 translocates to mitochondria and directly binds the coding sequence of ND2 mRNA (confirmed by luciferase reporter assay), reducing ND2 protein levels post-transcriptionally. Knockdown of ND2 phenocopies miR-762 overexpression (decreased ATP, increased ROS, reduced complex I activity, increased apoptosis), establishing ND2 as the functional target of miR-762 in cardiomyocyte mitochondrial dysfunction.","method":"miRNA microarray, luciferase reporter assay, siRNA knockdown, ATP/ROS measurement, complex I activity assay, apoptosis assay, mouse I/R injury model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — luciferase reporter directly validates miR-762 binding to ND2 CDS; knockdown rescue experiments confirm pathway; multiple orthogonal phenotypic readouts","pmids":["31235686"],"is_preprint":false},{"year":2019,"finding":"MITRAC15/COA1 is required for translation of the mitochondrial-encoded complex I subunit ND2; MITRAC15 is a constituent of a ribosome-nascent chain complex during ND2 translation. Chemical crosslinking showed that the ND2-specific assembly factor ACAD9 binds the ND2 C-terminus downstream of MITRAC15, placing MITRAC15-ribosome-nascent chain complex upstream of ACAD9 in the ND2 biogenesis pathway.","method":"MITRAC15 knockout, ribosome-nascent chain complex analysis, chemical crosslinking, assembly factor interaction analysis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 — KO demonstrates requirement; ribosome-nascent chain complex directly captures co-translational event; crosslinking defines sequential assembly factor binding order","pmids":["31721420"],"is_preprint":false},{"year":2022,"finding":"Sideroflexin 4 (SFXN4) interacts with the MCIA (mitochondrial complex I assembly) complex and is specifically required for assembly of the ND2 module of complex I, explaining why SFXN4 mutations cause mitochondrial disease.","method":"SFXN4 interaction studies with MCIA complex, complex I assembly analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — functional KO with defined molecular phenotype; interaction with MCIA complex; single study","pmids":["35333655"],"is_preprint":false},{"year":2013,"finding":"In E. coli NDH-1, the ND2 homolog NuoN functions in proton translocation: Lys395 (conserved in NuoN and NuoL but replaced in NuoM) participates in proton translocation; Glu133 in NuoN bears a functional role similar to Glu144 in NuoL/NuoM but its mutation can be compensated by nearby Glu72; conserved prolines in loop regions of discontinuous transmembrane helices play a similar role to those in NuoL and NuoM; the C-terminal amphipathic segments of NuoN TM14 interact with the Mβ sheet. These data suggest NuoL, NuoM, and NuoN pump protons by a similar mechanism.","method":"Site-directed mutagenesis, energy-transducing activity assays (NADH oxidase, ATP synthesis), truncation studies in E. coli","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with functional assays; multiple residues tested; mechanistic conclusions about proton translocation mechanism","pmids":["23864658"],"is_preprint":false},{"year":2026,"finding":"In E. coli NuoN (ND2 homolog), Lys247 and Lys395 are absolutely essential for both electron transfer and proton pumping activities; Lys217 mutation reduces NADH oxidase activity ~50% without reducing proton pumping; Glu133 mutation has no significant effect alone. A ΔNuoN complex I can be purified and retains ~30% activity when reconstituted into membranes containing ND2, demonstrating ND2/NuoN plays an essential role in the coupling mechanism between electron transfer and proton translocation.","method":"Site-directed mutagenesis, NuoN knockout, CI purification, instant membrane reconstitution, proteoliposome reconstitution, blue native PAGE","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro system, mutagenesis of multiple specific residues, both electron transfer and proton pumping measured independently","pmids":["41977177"],"is_preprint":false},{"year":2005,"finding":"A single nucleotide polymorphism in mt-Nd2 (encoding Leu276Met substitution in NADH dehydrogenase 2) in ALR mice confers resistance to both chemically induced (alloxan) and autoimmune type 1 diabetes; backcross experiments showed four-fold lower diabetes frequency when ALR contributed mtDNA, and shared alleles in mt-Co3 and mt-Tr allowed exclusion of other candidate mitochondrial genes.","method":"Reciprocal F1 crosses and backcrosses, mtDNA sequencing, genetic epistasis analysis","journal":"Diabetologia","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis/backcross design implicates specific SNP; candidate gene exclusion strengthens attribution; mechanism downstream not fully resolved","pmids":["15692809"],"is_preprint":false},{"year":2014,"finding":"ND2 is up-regulated at synaptic postsynaptic density compartments (co-localizing with PSD-95) within 60 min after spinal nerve ligation, and co-localizes with phosphorylated NR1 (pNMDA). Spinal superfusion with rotenone (ND2 inhibitor) prevented ND2 up-regulation and pNR1 up-regulation at synapses and abolished NMDAR/5-HT2B receptor-evoked field potentials, establishing ND2's role in coupling serotonergic input to NMDAR phosphorylation during neuropathic pain.","method":"Immunofluorescence co-localization, western blot (subcellular fractionation), spinal superfusion with rotenone, electrophysiology (field potentials)","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization with functional consequence; pharmacological inhibition with phenotypic readout; single lab, multiple methods","pmids":["24560713"],"is_preprint":false},{"year":2019,"finding":"ND2 mutations in L929dt cells disrupt mitochondrial supercomplex assembly (especially complexes containing complex I) and shift metabolism toward glycolysis; cybrids with L929dt mitochondria in L929 nuclear background reproduce all L929dt properties including higher tumorigenic and metastatic potential, demonstrating mitochondrial ND2 mutations are causally responsible for the aggressive tumor phenotype.","method":"Cybrid generation, OXPHOS measurement, supercomplex assembly analysis, in vivo tumor and metastasis assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — cybrid approach establishes mitochondrial causation; supercomplex assembly directly measured; in vivo functional readout","pmids":["31330915"],"is_preprint":false},{"year":1993,"finding":"The ND2 gene product of bovine complex I was identified as an Mr ~30,000 polypeptide in the hydrophobic protein fraction; purification was achieved by chloroform-methanol (2:1) extraction. The antiserum against purified bovine ND2 cross-reacted with an Mr ~39,000 polypeptide from Paracoccus denitrificans membranes, confirming evolutionary conservation.","method":"Amino acid analysis, partial N-terminal sequencing, chloroform-methanol extraction, immunological cross-reactivity","journal":"Biochemistry and molecular biology international","confidence":"Medium","confidence_rationale":"Tier 1-2 — direct protein purification and biochemical identification; evolutionary conservation confirmed by cross-reactivity","pmids":["8364407"],"is_preprint":false},{"year":2021,"finding":"The MT-ND2 m.5178C>A mutation in human lymphocyte lines increases ATP synthesis, decreases ROS production, increases mitochondrial membrane potential, increases Bcl-2 expression, decreases Caspase 3/7 activity, and increases oxygen consumption rate (basal, ATP-linked, maximal) compared to controls. Complex I activity is increased in mutant cells, establishing that this polymorphism protects mitochondrial function.","method":"Immortalized lymphocyte lines, ATP synthesis assay, ROS measurement, mitochondrial membrane potential, Seahorse OCR, Complex I activity assay, apoptosis assay","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal functional readouts; cell-based model; single lab","pmids":["34336093"],"is_preprint":false}],"current_model":"MT-ND2 encodes a core hydrophobic subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) that (1) functions as an antiporter-like proton-translocating subunit in the membrane arm via conserved lysine residues (Lys247, Lys395 in the E. coli homolog NuoN) essential for coupling electron transfer to proton pumping; (2) participates in the inhibitor/quinone-binding region of complex I (directly photolabeled by asimicin analogue, competed by rotenone); (3) acts as a founder/nucleating subunit for complex I assembly, with its translation regulated co-translationally by MITRAC15 and subsequent recruitment of ACAD9; (4) serves as a non-canonical adaptor protein anchoring Src kinase to NMDA receptors at neuronal synapses to regulate receptor phosphorylation and activity; and (5) influences mitochondrial ROS production through nuclear-mitochondrial epistasis, with specific polymorphisms modulating ROS output and susceptibility to autoimmune diabetes and other diseases."},"narrative":{"teleology":[{"year":1993,"claim":"Identification of ND2 as a hydrophobic ~30 kDa polypeptide subunit of bovine complex I with evolutionary conservation to Paracoccus established the biochemical identity of the gene product.","evidence":"Chloroform-methanol extraction, amino acid analysis, cross-reactive antiserum against Paracoccus membranes","pmids":["8364407"],"confidence":"Medium","gaps":["No functional assay performed","Stoichiometry within complex I not determined"]},{"year":2005,"claim":"A mt-Nd2 Leu276Met polymorphism in ALR mice was genetically linked to resistance to type 1 diabetes through backcross and epistasis analysis, establishing ND2 variation as a determinant of disease susceptibility.","evidence":"Reciprocal F1 crosses and backcrosses in NOD/ALR mice, mtDNA sequencing, candidate gene exclusion","pmids":["15692809"],"confidence":"Medium","gaps":["Molecular mechanism by which L276M alters complex I function not defined","Not replicated in independent mouse cohorts"]},{"year":2006,"claim":"Two independent lines of evidence established ND2 as central to complex I biology: a pathogenic L71P mutation arrested assembly at specific intermediates, and nuclear-mitochondrial epistasis involving mt-Nd2 alleles controlled mitochondrial ROS output.","evidence":"2D-BN-SDS-PAGE in transmitochondrial cybrids (assembly); conplastic mouse strains with ROS/respiration measurements","pmids":["16996290","17189252"],"confidence":"High","gaps":["Identity of other subunits in stalled assembly intermediates not fully resolved","Whether ROS modulation is solely attributable to ND2 or involves linked mtDNA variants"]},{"year":2010,"claim":"Photoaffinity labeling placed ND2 directly at the inhibitor/quinone-binding pocket of complex I, answering where within the membrane arm substrates and inhibitors interact.","evidence":"Photoaffinity crosslinking with [³H]benzophenone-asimicin; rotenone competition; 3D BN/SDS-PAGE separation","pmids":["20074573"],"confidence":"High","gaps":["Precise residues contacted by the photoaffinity probe on ND2 not mapped","Relationship between quinone-binding site and proton-pumping channel not resolved"]},{"year":2013,"claim":"Systematic mutagenesis of the E. coli ND2 homolog NuoN revealed conserved lysines and prolines that participate in proton translocation through discontinuous transmembrane helices, establishing a shared pumping mechanism with NuoL and NuoM.","evidence":"Site-directed mutagenesis of NuoN in E. coli; NADH oxidase and ATP synthesis assays; truncation analysis","pmids":["23864658"],"confidence":"High","gaps":["Proton pathway through NuoN not structurally visualized at the time","Functional compensation by nearby glutamates complicates assignment of individual residue contributions"]},{"year":2014,"claim":"ND2 was found to be rapidly upregulated at synaptic postsynaptic densities where it co-localizes with phosphorylated NMDA receptors, and rotenone blocked both ND2 accumulation and NMDAR phosphorylation, revealing a non-canonical synaptic signaling function.","evidence":"Immunofluorescence co-localization with PSD-95 and pNR1, subcellular fractionation, spinal superfusion with rotenone, field potential electrophysiology","pmids":["24560713"],"confidence":"Medium","gaps":["Rotenone is not ND2-specific and may affect other complex I functions","Mechanism of ND2 trafficking to postsynaptic density not defined"]},{"year":2017,"claim":"Structural and functional experiments demonstrated that ND2 acts as an adaptor anchoring Src kinase to the GluN1 subunit of NMDA receptors, enabled by the evolutionary loss of three transmembrane helices in bilaterians; a blocking peptide confirmed functional significance.","evidence":"Homology modeling, computational docking, ND2 fragment peptide blocking experiments, neuronal electrophysiology","pmids":["28508887"],"confidence":"High","gaps":["Direct structural determination of ND2-Src-GluN1 ternary complex not available","How ND2 exits the mitochondria to reach the plasma membrane not explained"]},{"year":2019,"claim":"The co-translational assembly pathway of ND2 was defined: MITRAC15 associates with the ribosome-nascent chain complex during ND2 translation, followed by ACAD9 binding to the ND2 C-terminus, ordering the earliest steps of complex I membrane arm biogenesis.","evidence":"MITRAC15 knockout, ribosome-nascent chain complex analysis, chemical crosslinking","pmids":["31721420"],"confidence":"High","gaps":["Structural basis of MITRAC15 recognition of the ND2 nascent chain unknown","Whether additional ribosome-associated factors participate not tested"]},{"year":2019,"claim":"Post-transcriptional regulation of ND2 by mitochondria-localized miR-762 was established, with miR-762 binding the ND2 coding sequence to reduce protein levels, and ND2 knockdown phenocopying the resulting mitochondrial dysfunction in cardiomyocytes.","evidence":"Luciferase reporter assay, siRNA knockdown, ATP/ROS/complex I activity assays, mouse ischemia-reperfusion model","pmids":["31235686"],"confidence":"High","gaps":["Whether miR-762-mediated ND2 regulation occurs in non-cardiac cell types unknown","Stoichiometric impact on complex I assembly not assessed"]},{"year":2019,"claim":"ND2 mutations in L929dt cells were shown to disrupt supercomplex assembly and shift metabolism toward glycolysis, with cybrid transfer proving mitochondrial ND2 mutations are causally responsible for increased tumorigenicity and metastatic potential.","evidence":"Cybrid generation, OXPHOS and supercomplex analysis, in vivo tumor/metastasis assays","pmids":["31330915"],"confidence":"Medium","gaps":["Specific ND2 mutations not individually characterized for contribution","Whether supercomplex disruption or metabolic shift drives tumorigenicity not dissected"]},{"year":2022,"claim":"SFXN4 was identified as an additional assembly factor specifically required for the ND2 module of complex I through its interaction with the MCIA complex, expanding the known assembly machinery.","evidence":"SFXN4 interaction studies with MCIA complex, complex I assembly analysis","pmids":["35333655"],"confidence":"Medium","gaps":["Direct physical interaction between SFXN4 and ND2 not demonstrated","Single study; independent replication needed"]},{"year":2026,"claim":"Reconstitution of purified ΔNuoN complex I into proteoliposomes definitively proved ND2/NuoN is essential for coupling electron transfer to proton translocation, with Lys247 and Lys395 absolutely required for both activities.","evidence":"NuoN knockout, complex I purification, instant membrane and proteoliposome reconstitution, independent measurement of electron transfer and proton pumping","pmids":["41977177"],"confidence":"High","gaps":["Whether all four proton-pumping subunits operate by identical conformational mechanism remains unresolved","Human ND2-specific reconstitution not yet performed"]},{"year":null,"claim":"How ND2 exits the mitochondrial inner membrane to function as a synaptic adaptor at the plasma membrane remains mechanistically unexplained, and no structural determination of the mammalian ND2-Src-GluN1 complex exists.","evidence":"","pmids":[],"confidence":"Low","gaps":["Trafficking mechanism of ND2 to extramitochondrial locations unknown","No high-resolution structure of mammalian ND2 in the adaptor conformation","Relative physiological importance of ND2's bioenergetic vs. signaling roles not quantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[7,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,10]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,5,7,8,12]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,10]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,7,8,13]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,5,6]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,10]}],"complexes":["Mitochondrial complex I (NADH:ubiquinone oxidoreductase)","NMDAR-Src-ND2 signaling complex"],"partners":["MITRAC15","ACAD9","SFXN4","SRC","GRIN1"],"other_free_text":[]},"mechanistic_narrative":"MT-ND2 encodes a core hydrophobic subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) that functions as an antiporter-like proton-translocating module in the membrane arm, with conserved lysine residues (Lys247, Lys395 in E. coli NuoN) essential for coupling electron transfer to proton pumping [PMID:23864658, PMID:41977177]. ND2 participates in the inhibitor/quinone-binding region of complex I, as demonstrated by direct photoaffinity labeling with an asimicin analogue that is competed by rotenone [PMID:20074573]. The subunit serves as a nucleating element for complex I assembly, with its translation regulated co-translationally by MITRAC15 followed by sequential recruitment of ACAD9 and the MCIA complex, and pathogenic missense mutations in ND2 block assembly at defined intermediates [PMID:16996290, PMID:31721420, PMID:35333655]. Beyond its canonical bioenergetic role, ND2 functions as a non-canonical adaptor protein at neuronal synapses, anchoring Src kinase to the NMDA receptor GluN1 subunit to regulate receptor phosphorylation and synaptic currents [PMID:28508887, PMID:24560713]."},"prefetch_data":{"uniprot":{"accession":"P03891","full_name":"NADH-ubiquinone oxidoreductase chain 2","aliases":["NADH dehydrogenase subunit 2"],"length_aa":347,"mass_kda":39.0,"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 (PubMed:16996290). Essential for the catalytic activity and assembly of complex I (PubMed:16996290)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/P03891/entry"},"depmap":{"release":"DepMap","has_data":false,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MT-ND2"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MT-ND2","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":107283.0},{"tissue":"heart muscle","ntpm":130852.9}],"url":"https://www.proteinatlas.org/search/MT-ND2"},"hgnc":{"alias_symbol":["ND2","NAD2"],"prev_symbol":["MTND2"]},"alphafold":{"accession":"P03891","domains":[{"cath_id":"-","chopping":"1-149","consensus_level":"medium","plddt":95.3615,"start":1,"end":149},{"cath_id":"-","chopping":"151-347","consensus_level":"medium","plddt":94.9541,"start":151,"end":347}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P03891","model_url":"https://alphafold.ebi.ac.uk/files/AF-P03891-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P03891-F1-predicted_aligned_error_v6.png","plddt_mean":95.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MT-ND2","jax_strain_url":"https://www.jax.org/strain/search?query=MT-ND2"},"sequence":{"accession":"P03891","fasta_url":"https://rest.uniprot.org/uniprotkb/P03891.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P03891/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P03891"}},"corpus_meta":[{"pmid":"20561255","id":"PMC_20561255","title":"ABA 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First report from Sialkot District of Pakistan.","date":"2022","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/36584819","citation_count":0,"is_preprint":false},{"pmid":"40450641","id":"PMC_40450641","title":"Genetic Variants Within ND2 Gene of Mitochondria are Associated with the Altered Levels of Ammonia, Vitamin D and Free Thyroxine in Bangladeshi Children with Autism Spectrum Disorder.","date":"2025","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40450641","citation_count":0,"is_preprint":false},{"pmid":"41977177","id":"PMC_41977177","title":"Roles of Subunit ND2/NuoN in the Proton Pumping Coupling Mechanism of Complex I.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41977177","citation_count":0,"is_preprint":false},{"pmid":"41891495","id":"PMC_41891495","title":"Cardioprotective Effects of Cuminaldehyde Mitigate Isoproterenol-Induced Myocardial Infarction by Modulating the PGC-1α/ND2-Mediated Mitochondrial and eNOS/NO/VCAM-1- Mediated Endothelial Dysfunction Pathways.","date":"2026","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/41891495","citation_count":0,"is_preprint":false},{"pmid":"1380634","id":"PMC_1380634","title":"[Immunohistochemical study and biodistribution of monoclonal antibody (Nd2) against human pancreatic cancer].","date":"1992","source":"Nihon Geka Gakkai zasshi","url":"https://pubmed.ncbi.nlm.nih.gov/1380634","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.09.25331017","title":"Early-Phase Fluid Diagnostic Biomarkers in Acute Ischemic Stroke: An Umbrella Review","date":"2025-07-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.09.25331017","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47482,"output_tokens":3752,"usd":0.099363},"stage2":{"model":"claude-opus-4-6","input_tokens":7136,"output_tokens":3002,"usd":0.166095},"total_usd":0.265458,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"A missense mutation (T4681C) in mitochondrial ND2 causing L71P substitution disrupts complex I assembly, leading to accumulation of specific assembly intermediates as shown by 2D blue native/SDS-PAGE, demonstrating ND2 is required for proper complex I assembly pathway.\",\n      \"method\": \"2D-BN-SDS-PAGE, transmitochondrial cybrid clones, biochemical complex I activity assay\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cybrid clones confirm mitochondrial genetic origin; 2D-BN-PAGE directly visualizes assembly intermediates; multiple orthogonal methods\",\n      \"pmids\": [\"16996290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nuclear-mitochondrial interaction involving mt-Nd2 alleles controls mitochondrial reactive oxygen species production: ALR.mt(NOD) conplastic mice (NOD mtDNA on ALR nuclear background) produced significantly more ROS with complex I or complex II substrates compared to parental strains, establishing mt-Nd2 as a critical regulator of mitochondrial ROS output.\",\n      \"method\": \"Reciprocal conplastic mouse strains, mitochondrial respiration assay, ROS measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal conplastic design isolates mitochondrial genome contribution; multiple substrate conditions tested; strong mechanistic interpretation\",\n      \"pmids\": [\"17189252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ND2 subunit is directly labeled by photoaffinity analogue of asimicin ([3H]BPA), a potent complex I inhibitor, identifying ND2 as part of the inhibitor/quinone-binding region of complex I; cross-linking was blocked by rotenone.\",\n      \"method\": \"Photoaffinity labeling with [3H]benzophenone-asimicin, 3D separation by blue-native/doubled SDS-PAGE\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct photoaffinity crosslinking in vitro with competition control (rotenone blockade); identifies ND2 at inhibitor/quinone binding site\",\n      \"pmids\": [\"20074573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ND2 serves as a mitochondrially encoded adaptor protein that anchors Src kinase within the NMDA receptor complex via interaction with the transmembrane domain of GluN1; this interaction is enabled by the evolutionary loss of three helices in bilaterian ND2. Blocking this interaction with an ND2 fragment prevents Src-mediated upregulation of NMDAR currents in neurons.\",\n      \"method\": \"Homology modeling, computational docking, experimental validation with ND2 fragment peptide, electrophysiology in neurons\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structural modeling validated experimentally; functional readout (NMDAR currents) confirmed; mechanistic peptide blocking experiment\",\n      \"pmids\": [\"28508887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-762 translocates to mitochondria and directly binds the coding sequence of ND2 mRNA (confirmed by luciferase reporter assay), reducing ND2 protein levels post-transcriptionally. Knockdown of ND2 phenocopies miR-762 overexpression (decreased ATP, increased ROS, reduced complex I activity, increased apoptosis), establishing ND2 as the functional target of miR-762 in cardiomyocyte mitochondrial dysfunction.\",\n      \"method\": \"miRNA microarray, luciferase reporter assay, siRNA knockdown, ATP/ROS measurement, complex I activity assay, apoptosis assay, mouse I/R injury model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — luciferase reporter directly validates miR-762 binding to ND2 CDS; knockdown rescue experiments confirm pathway; multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"31235686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MITRAC15/COA1 is required for translation of the mitochondrial-encoded complex I subunit ND2; MITRAC15 is a constituent of a ribosome-nascent chain complex during ND2 translation. Chemical crosslinking showed that the ND2-specific assembly factor ACAD9 binds the ND2 C-terminus downstream of MITRAC15, placing MITRAC15-ribosome-nascent chain complex upstream of ACAD9 in the ND2 biogenesis pathway.\",\n      \"method\": \"MITRAC15 knockout, ribosome-nascent chain complex analysis, chemical crosslinking, assembly factor interaction analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KO demonstrates requirement; ribosome-nascent chain complex directly captures co-translational event; crosslinking defines sequential assembly factor binding order\",\n      \"pmids\": [\"31721420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sideroflexin 4 (SFXN4) interacts with the MCIA (mitochondrial complex I assembly) complex and is specifically required for assembly of the ND2 module of complex I, explaining why SFXN4 mutations cause mitochondrial disease.\",\n      \"method\": \"SFXN4 interaction studies with MCIA complex, complex I assembly analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional KO with defined molecular phenotype; interaction with MCIA complex; single study\",\n      \"pmids\": [\"35333655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In E. coli NDH-1, the ND2 homolog NuoN functions in proton translocation: Lys395 (conserved in NuoN and NuoL but replaced in NuoM) participates in proton translocation; Glu133 in NuoN bears a functional role similar to Glu144 in NuoL/NuoM but its mutation can be compensated by nearby Glu72; conserved prolines in loop regions of discontinuous transmembrane helices play a similar role to those in NuoL and NuoM; the C-terminal amphipathic segments of NuoN TM14 interact with the Mβ sheet. These data suggest NuoL, NuoM, and NuoN pump protons by a similar mechanism.\",\n      \"method\": \"Site-directed mutagenesis, energy-transducing activity assays (NADH oxidase, ATP synthesis), truncation studies in E. coli\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with functional assays; multiple residues tested; mechanistic conclusions about proton translocation mechanism\",\n      \"pmids\": [\"23864658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In E. coli NuoN (ND2 homolog), Lys247 and Lys395 are absolutely essential for both electron transfer and proton pumping activities; Lys217 mutation reduces NADH oxidase activity ~50% without reducing proton pumping; Glu133 mutation has no significant effect alone. A ΔNuoN complex I can be purified and retains ~30% activity when reconstituted into membranes containing ND2, demonstrating ND2/NuoN plays an essential role in the coupling mechanism between electron transfer and proton translocation.\",\n      \"method\": \"Site-directed mutagenesis, NuoN knockout, CI purification, instant membrane reconstitution, proteoliposome reconstitution, blue native PAGE\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro system, mutagenesis of multiple specific residues, both electron transfer and proton pumping measured independently\",\n      \"pmids\": [\"41977177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A single nucleotide polymorphism in mt-Nd2 (encoding Leu276Met substitution in NADH dehydrogenase 2) in ALR mice confers resistance to both chemically induced (alloxan) and autoimmune type 1 diabetes; backcross experiments showed four-fold lower diabetes frequency when ALR contributed mtDNA, and shared alleles in mt-Co3 and mt-Tr allowed exclusion of other candidate mitochondrial genes.\",\n      \"method\": \"Reciprocal F1 crosses and backcrosses, mtDNA sequencing, genetic epistasis analysis\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis/backcross design implicates specific SNP; candidate gene exclusion strengthens attribution; mechanism downstream not fully resolved\",\n      \"pmids\": [\"15692809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ND2 is up-regulated at synaptic postsynaptic density compartments (co-localizing with PSD-95) within 60 min after spinal nerve ligation, and co-localizes with phosphorylated NR1 (pNMDA). Spinal superfusion with rotenone (ND2 inhibitor) prevented ND2 up-regulation and pNR1 up-regulation at synapses and abolished NMDAR/5-HT2B receptor-evoked field potentials, establishing ND2's role in coupling serotonergic input to NMDAR phosphorylation during neuropathic pain.\",\n      \"method\": \"Immunofluorescence co-localization, western blot (subcellular fractionation), spinal superfusion with rotenone, electrophysiology (field potentials)\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization with functional consequence; pharmacological inhibition with phenotypic readout; single lab, multiple methods\",\n      \"pmids\": [\"24560713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ND2 mutations in L929dt cells disrupt mitochondrial supercomplex assembly (especially complexes containing complex I) and shift metabolism toward glycolysis; cybrids with L929dt mitochondria in L929 nuclear background reproduce all L929dt properties including higher tumorigenic and metastatic potential, demonstrating mitochondrial ND2 mutations are causally responsible for the aggressive tumor phenotype.\",\n      \"method\": \"Cybrid generation, OXPHOS measurement, supercomplex assembly analysis, in vivo tumor and metastasis assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cybrid approach establishes mitochondrial causation; supercomplex assembly directly measured; in vivo functional readout\",\n      \"pmids\": [\"31330915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The ND2 gene product of bovine complex I was identified as an Mr ~30,000 polypeptide in the hydrophobic protein fraction; purification was achieved by chloroform-methanol (2:1) extraction. The antiserum against purified bovine ND2 cross-reacted with an Mr ~39,000 polypeptide from Paracoccus denitrificans membranes, confirming evolutionary conservation.\",\n      \"method\": \"Amino acid analysis, partial N-terminal sequencing, chloroform-methanol extraction, immunological cross-reactivity\",\n      \"journal\": \"Biochemistry and molecular biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct protein purification and biochemical identification; evolutionary conservation confirmed by cross-reactivity\",\n      \"pmids\": [\"8364407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The MT-ND2 m.5178C>A mutation in human lymphocyte lines increases ATP synthesis, decreases ROS production, increases mitochondrial membrane potential, increases Bcl-2 expression, decreases Caspase 3/7 activity, and increases oxygen consumption rate (basal, ATP-linked, maximal) compared to controls. Complex I activity is increased in mutant cells, establishing that this polymorphism protects mitochondrial function.\",\n      \"method\": \"Immortalized lymphocyte lines, ATP synthesis assay, ROS measurement, mitochondrial membrane potential, Seahorse OCR, Complex I activity assay, apoptosis assay\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional readouts; cell-based model; single lab\",\n      \"pmids\": [\"34336093\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MT-ND2 encodes a core hydrophobic subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) that (1) functions as an antiporter-like proton-translocating subunit in the membrane arm via conserved lysine residues (Lys247, Lys395 in the E. coli homolog NuoN) essential for coupling electron transfer to proton pumping; (2) participates in the inhibitor/quinone-binding region of complex I (directly photolabeled by asimicin analogue, competed by rotenone); (3) acts as a founder/nucleating subunit for complex I assembly, with its translation regulated co-translationally by MITRAC15 and subsequent recruitment of ACAD9; (4) serves as a non-canonical adaptor protein anchoring Src kinase to NMDA receptors at neuronal synapses to regulate receptor phosphorylation and activity; and (5) influences mitochondrial ROS production through nuclear-mitochondrial epistasis, with specific polymorphisms modulating ROS output and susceptibility to autoimmune diabetes and other diseases.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MT-ND2 encodes a core hydrophobic subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) that functions as an antiporter-like proton-translocating module in the membrane arm, with conserved lysine residues (Lys247, Lys395 in E. coli NuoN) essential for coupling electron transfer to proton pumping [PMID:23864658, PMID:41977177]. ND2 participates in the inhibitor/quinone-binding region of complex I, as demonstrated by direct photoaffinity labeling with an asimicin analogue that is competed by rotenone [PMID:20074573]. The subunit serves as a nucleating element for complex I assembly, with its translation regulated co-translationally by MITRAC15 followed by sequential recruitment of ACAD9 and the MCIA complex, and pathogenic missense mutations in ND2 block assembly at defined intermediates [PMID:16996290, PMID:31721420, PMID:35333655]. Beyond its canonical bioenergetic role, ND2 functions as a non-canonical adaptor protein at neuronal synapses, anchoring Src kinase to the NMDA receptor GluN1 subunit to regulate receptor phosphorylation and synaptic currents [PMID:28508887, PMID:24560713].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Identification of ND2 as a hydrophobic ~30 kDa polypeptide subunit of bovine complex I with evolutionary conservation to Paracoccus established the biochemical identity of the gene product.\",\n      \"evidence\": \"Chloroform-methanol extraction, amino acid analysis, cross-reactive antiserum against Paracoccus membranes\",\n      \"pmids\": [\"8364407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assay performed\", \"Stoichiometry within complex I not determined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"A mt-Nd2 Leu276Met polymorphism in ALR mice was genetically linked to resistance to type 1 diabetes through backcross and epistasis analysis, establishing ND2 variation as a determinant of disease susceptibility.\",\n      \"evidence\": \"Reciprocal F1 crosses and backcrosses in NOD/ALR mice, mtDNA sequencing, candidate gene exclusion\",\n      \"pmids\": [\"15692809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which L276M alters complex I function not defined\", \"Not replicated in independent mouse cohorts\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Two independent lines of evidence established ND2 as central to complex I biology: a pathogenic L71P mutation arrested assembly at specific intermediates, and nuclear-mitochondrial epistasis involving mt-Nd2 alleles controlled mitochondrial ROS output.\",\n      \"evidence\": \"2D-BN-SDS-PAGE in transmitochondrial cybrids (assembly); conplastic mouse strains with ROS/respiration measurements\",\n      \"pmids\": [\"16996290\", \"17189252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of other subunits in stalled assembly intermediates not fully resolved\", \"Whether ROS modulation is solely attributable to ND2 or involves linked mtDNA variants\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Photoaffinity labeling placed ND2 directly at the inhibitor/quinone-binding pocket of complex I, answering where within the membrane arm substrates and inhibitors interact.\",\n      \"evidence\": \"Photoaffinity crosslinking with [³H]benzophenone-asimicin; rotenone competition; 3D BN/SDS-PAGE separation\",\n      \"pmids\": [\"20074573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise residues contacted by the photoaffinity probe on ND2 not mapped\", \"Relationship between quinone-binding site and proton-pumping channel not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Systematic mutagenesis of the E. coli ND2 homolog NuoN revealed conserved lysines and prolines that participate in proton translocation through discontinuous transmembrane helices, establishing a shared pumping mechanism with NuoL and NuoM.\",\n      \"evidence\": \"Site-directed mutagenesis of NuoN in E. coli; NADH oxidase and ATP synthesis assays; truncation analysis\",\n      \"pmids\": [\"23864658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Proton pathway through NuoN not structurally visualized at the time\", \"Functional compensation by nearby glutamates complicates assignment of individual residue contributions\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"ND2 was found to be rapidly upregulated at synaptic postsynaptic densities where it co-localizes with phosphorylated NMDA receptors, and rotenone blocked both ND2 accumulation and NMDAR phosphorylation, revealing a non-canonical synaptic signaling function.\",\n      \"evidence\": \"Immunofluorescence co-localization with PSD-95 and pNR1, subcellular fractionation, spinal superfusion with rotenone, field potential electrophysiology\",\n      \"pmids\": [\"24560713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Rotenone is not ND2-specific and may affect other complex I functions\", \"Mechanism of ND2 trafficking to postsynaptic density not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Structural and functional experiments demonstrated that ND2 acts as an adaptor anchoring Src kinase to the GluN1 subunit of NMDA receptors, enabled by the evolutionary loss of three transmembrane helices in bilaterians; a blocking peptide confirmed functional significance.\",\n      \"evidence\": \"Homology modeling, computational docking, ND2 fragment peptide blocking experiments, neuronal electrophysiology\",\n      \"pmids\": [\"28508887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural determination of ND2-Src-GluN1 ternary complex not available\", \"How ND2 exits the mitochondria to reach the plasma membrane not explained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The co-translational assembly pathway of ND2 was defined: MITRAC15 associates with the ribosome-nascent chain complex during ND2 translation, followed by ACAD9 binding to the ND2 C-terminus, ordering the earliest steps of complex I membrane arm biogenesis.\",\n      \"evidence\": \"MITRAC15 knockout, ribosome-nascent chain complex analysis, chemical crosslinking\",\n      \"pmids\": [\"31721420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MITRAC15 recognition of the ND2 nascent chain unknown\", \"Whether additional ribosome-associated factors participate not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Post-transcriptional regulation of ND2 by mitochondria-localized miR-762 was established, with miR-762 binding the ND2 coding sequence to reduce protein levels, and ND2 knockdown phenocopying the resulting mitochondrial dysfunction in cardiomyocytes.\",\n      \"evidence\": \"Luciferase reporter assay, siRNA knockdown, ATP/ROS/complex I activity assays, mouse ischemia-reperfusion model\",\n      \"pmids\": [\"31235686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether miR-762-mediated ND2 regulation occurs in non-cardiac cell types unknown\", \"Stoichiometric impact on complex I assembly not assessed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ND2 mutations in L929dt cells were shown to disrupt supercomplex assembly and shift metabolism toward glycolysis, with cybrid transfer proving mitochondrial ND2 mutations are causally responsible for increased tumorigenicity and metastatic potential.\",\n      \"evidence\": \"Cybrid generation, OXPHOS and supercomplex analysis, in vivo tumor/metastasis assays\",\n      \"pmids\": [\"31330915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ND2 mutations not individually characterized for contribution\", \"Whether supercomplex disruption or metabolic shift drives tumorigenicity not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"SFXN4 was identified as an additional assembly factor specifically required for the ND2 module of complex I through its interaction with the MCIA complex, expanding the known assembly machinery.\",\n      \"evidence\": \"SFXN4 interaction studies with MCIA complex, complex I assembly analysis\",\n      \"pmids\": [\"35333655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between SFXN4 and ND2 not demonstrated\", \"Single study; independent replication needed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Reconstitution of purified ΔNuoN complex I into proteoliposomes definitively proved ND2/NuoN is essential for coupling electron transfer to proton translocation, with Lys247 and Lys395 absolutely required for both activities.\",\n      \"evidence\": \"NuoN knockout, complex I purification, instant membrane and proteoliposome reconstitution, independent measurement of electron transfer and proton pumping\",\n      \"pmids\": [\"41977177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all four proton-pumping subunits operate by identical conformational mechanism remains unresolved\", \"Human ND2-specific reconstitution not yet performed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ND2 exits the mitochondrial inner membrane to function as a synaptic adaptor at the plasma membrane remains mechanistically unexplained, and no structural determination of the mammalian ND2-Src-GluN1 complex exists.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Trafficking mechanism of ND2 to extramitochondrial locations unknown\", \"No high-resolution structure of mammalian ND2 in the adaptor conformation\", \"Relative physiological importance of ND2's bioenergetic vs. signaling roles not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 5, 7, 8, 12]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 7, 8, 13]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"complexes\": [\n      \"Mitochondrial complex I (NADH:ubiquinone oxidoreductase)\",\n      \"NMDAR-Src-ND2 signaling complex\"\n    ],\n    \"partners\": [\n      \"MITRAC15\",\n      \"ACAD9\",\n      \"SFXN4\",\n      \"SRC\",\n      \"GRIN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}