{"gene":"NDUFA13","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":2001,"finding":"GRIM-19/NDUFA13 is a bona fide subunit of bovine mitochondrial NADH:ubiquinone oxidoreductase (Complex I), identified by mass-spectrometric peptide sequencing of subcomplex Iλ (hydrophilic arm), with the N-terminus shown to be acetylated.","method":"Denaturing gel electrophoresis of Complex I subcomplex, tryptic digestion, mass spectrometry, cDNA cloning, intact protein mass measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical identification from purified complex with MS and sequencing","pmids":["11522775"],"is_preprint":false},{"year":2000,"finding":"GRIM-19 is induced by the IFN-β/retinoic acid combination and is required for IFN/RA-induced tumor cell death; antisense inactivation of GRIM-19 confers resistance to cell death and overexpression enhances it.","method":"Antisense knockout genetic screen, overexpression and antisense expression assays in tumor cell lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — original genetic screen with loss- and gain-of-function validation, foundational paper","pmids":["10924506"],"is_preprint":false},{"year":2003,"finding":"GRIM-19 physically interacts with STAT3 (but not STAT1 or STAT5a), co-localizes with STAT3 at perinuclear mitochondrial aggregates, inhibits STAT3 nuclear translocation stimulated by EGF, and represses STAT3 transcriptional activity and target gene expression.","method":"Yeast two-hybrid screen, co-immunoprecipitation, co-localization with mitochondrial markers, domain mapping, reporter assays, growth suppression assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction confirmed, multiple orthogonal methods in one study, replicated by independent lab (PMID:12867595)","pmids":["12628925","12867595"],"is_preprint":false},{"year":2003,"finding":"GRIM-19 binds specifically to STAT3 (not STAT1) via the STAT3 transactivation domain; residue S727 of STAT3 is required for GRIM-19 binding. GRIM-19 inhibits STAT3-driven transcription without blocking STAT3 tyrosine phosphorylation or DNA binding.","method":"Yeast two-hybrid screen, co-immunoprecipitation, point mutant analysis, reporter gene assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis defining binding residue, orthogonal interaction assays","pmids":["12867595"],"is_preprint":false},{"year":2004,"finding":"GRIM-19 is essential for Complex I assembly and electron transfer activity; homozygous knockout in mice causes embryonic lethality at E9.5 with abnormal mitochondrial structure and distribution, and loss of GRIM-19 destroys Complex I assembly and influences other respiratory chain complexes.","method":"Gene targeting/knockout mice, native Complex I immunoprecipitation, electron transfer activity assay, mitochondrial morphology analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean knockout with defined cellular and biochemical phenotypes, replicated in subsequent studies","pmids":["15367666"],"is_preprint":false},{"year":2008,"finding":"Functional domain mapping shows that the mitochondrial localization sequence of GRIM-19 is at its N-terminus; deletion of residues 70–80, 90–100, or the C-terminal region (70–144) abolishes mitochondrial transmembrane potential (ΔΨm); deletion of the last 10 C-terminal residues prevents assembly into Complex I; a dominant-negative mutant assembled into Complex I but failed to maintain ΔΨm and sensitized cells to apoptosis.","method":"Deletion/truncation/point mutant analysis, mitochondrial membrane potential assay, Complex I assembly assay, apoptosis assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — structure-function mutagenesis with multiple orthogonal functional readouts","pmids":["18287540"],"is_preprint":false},{"year":2012,"finding":"GRIM-19 acts as a chaperone to recruit STAT3 into the inner mitochondrial membrane and enhances STAT3 integration into Complex I; the STAT3 S727A mutation reduces import and Complex I assembly even in the presence of GRIM-19.","method":"In vitro mitochondrial import assay, sub-mitochondrial fractionation, co-immunoprecipitation, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro import reconstitution with mutagenesis validation","pmids":["23271731"],"is_preprint":false},{"year":2012,"finding":"During TNF-induced necroptosis, RIPK1-dependent phosphorylation of STAT3 on S727 induces its interaction with GRIM-19, leading to mitochondrial translocation of STAT3, increased mitochondrial ROS production, and cell death.","method":"siRNA knockdown of RIPK1, necrostatin-1 inhibition, phospho-specific immunoblotting, co-immunoprecipitation, mitochondrial fractionation, ROS measurement","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — epistasis with RIPK1, reciprocal Co-IP, mitochondrial fractionation, multiple orthogonal methods","pmids":["22393233"],"is_preprint":false},{"year":2002,"finding":"KSHV vIRF1 directly interacts with GRIM-19 via its N-terminal region, co-localizes with GRIM-19, deregulates GRIM-19-induced apoptosis, and inhibits IFN/RA-induced cell death; HPV16 E6 also binds GRIM-19.","method":"Yeast two-hybrid, co-immunoprecipitation (in vivo and in vitro), confocal co-localization, cell death assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal in vivo/in vitro interaction with functional cell death readout, single lab","pmids":["12163600"],"is_preprint":false},{"year":2005,"finding":"GRIM-19 interacts with NOD2 in intestinal epithelial cells and is required for NF-κB activation following NOD2-mediated recognition of muramyl dipeptide and for control of pathogen invasion.","method":"Yeast two-hybrid, endogenous co-immunoprecipitation in HT29 cells, siRNA knockdown, bacterial invasion assay, NF-κB reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — endogenous Co-IP with functional knockdown phenotype, single lab","pmids":["15753091"],"is_preprint":false},{"year":2007,"finding":"GRIM-19 physically interacts with the serine protease HtrA2, augments HtrA2-driven destruction of XIAP in an IFN/RA-dependent manner, and promotes cell death; vIRF1 disrupts this interaction to confer resistance to IFN/RA-induced death.","method":"Yeast two-hybrid, co-immunoprecipitation, cell death assay, XIAP degradation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — direct interaction with functional consequence, single lab","pmids":["17297443"],"is_preprint":false},{"year":2007,"finding":"GRIM-19 suppresses v-Src-induced cellular transformation and metastasis by inhibiting STAT3-dependent gene expression and by suppressing tyrosyl phosphorylation of focal adhesion kinase, paxillin, E-cadherin, and γ-catenin independently of STAT3.","method":"Overexpression and shRNA knockdown, in vitro transformation assay, in vivo metastasis assay, phospho-Western blotting","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — loss- and gain-of-function with in vivo validation, two distinct mechanisms identified","pmids":["17823279"],"is_preprint":false},{"year":2009,"finding":"GRIM-19 inhibits v-Src-induced cell motility and podosome formation through its N-terminal domain, independently of STAT3; tumor-associated GRIM-19 mutations disrupt this activity and fail to upregulate the lipid raft-associated Src inhibitor Pag1.","method":"N-terminal deletion and point mutant analysis, podosome formation assay, cell motility assay, in vivo metastasis assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — structure-function with in vivo metastasis readout, single lab","pmids":["19151760"],"is_preprint":false},{"year":2011,"finding":"GRIM-19 disrupts the HPV18 E6/E6AP complex by interacting with both E6 and E6AP via its N-terminus, promotes E6AP ubiquitination and degradation, and thereby rescues p53 from degradation and promotes apoptosis in cervical cancer cells.","method":"Co-immunoprecipitation, GST pull-down, competition pull-down assay, in vivo and in vitro ubiquitination assay, xenograft tumor model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical assays (pull-down, ubiquitination) with in vivo validation, single lab","pmids":["21765936"],"is_preprint":false},{"year":2012,"finding":"Heterozygous GRIM-19 knockout macrophages have compromised Complex I activity and elevated ROS, leading to decreased intracellular bacterial killing and reduced proinflammatory cytokine production; bacterial infection normally upregulates GRIM-19 and Complex I activity in wild-type macrophages.","method":"Heterozygous knockout mice, Complex I activity assay, ROS measurement, intracellular bacterial killing assay, cytokine ELISA, in vivo infection model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean genetic model with multiple biochemical and functional readouts","pmids":["22665480"],"is_preprint":false},{"year":2013,"finding":"Tumor-derived somatic mutations in GRIM-19 (L71P, L91P, A95T) cause loss of STAT3 binding, loss of suppression of STAT3 transcriptional activity, and failure to suppress cellular transformation and metastasis in vitro and in vivo.","method":"Somatic mutation screening of primary tumors, co-immunoprecipitation, transformation assay, in vivo tumor growth and metastasis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — structure-function with tumor-derived mutations, in vivo validation, single lab","pmids":["23386605"],"is_preprint":false},{"year":2013,"finding":"Monoallelic skin-specific deletion of GRIM-19 is sufficient to promote chemical carcinogenesis and invasive squamous cell carcinoma, associated with high STAT3 activity, upregulated STAT3-responsive genes, mitochondrial electron transport dysfunction, and failure to assemble ETC complexes.","method":"Conditional knockout mice, chemical carcinogenesis protocol, Complex I assembly assay, STAT3 activity assay, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo conditional KO with defined molecular and biochemical phenotypes","pmids":["24145455"],"is_preprint":false},{"year":2013,"finding":"GRIM-19 opposes the Warburg effect in glioblastoma by destabilizing HIF-1α: GRIM-19 loss promotes STAT3-dependent HIF-1α synthesis and prevents pVHL-mediated HIF-1α ubiquitination/proteasomal degradation.","method":"Overexpression/knockdown in glioblastoma cell lines, HIF-1α protein stability assays, pVHL interaction assay, STAT3 inhibitor","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2–3 — pathway placement via loss-of-function with mechanistic follow-up, single lab","pmids":["23580587"],"is_preprint":false},{"year":2015,"finding":"The first germline pathogenic mutation in NDUFA13/GRIM-19 is identified in patients with early onset hypotonia, dyskinesia, and optic neuropathy; patient cells show drastically reduced Complex I enzymatic activity, reduced CI-driven respiration, and loss of NDUFA13 protein, CI holoenzyme, and supercomplexes; NDUFA13 silencing in control cells reproduces CI instability.","method":"Patient mutation identification, biochemical analysis of muscle biopsies and fibroblasts, BN-PAGE for Complex I holoenzyme and supercomplexes, Western blot, siRNA knockdown","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 — patient genetics with biochemical reconstitution of phenotype by siRNA, multiple orthogonal assays","pmids":["25901006"],"is_preprint":false},{"year":2017,"finding":"Cardiac-specific heterozygous NDUFA13 knockout mice show basal-state cytosolic H2O2 elevation (not mitochondrial), which drives STAT3 dimerization and antiapoptotic signaling, reducing infarct size during ischemia-reperfusion injury; NDUFA13 is positioned near low-electrochemical-potential subunits of Complex I and mediates electron leak.","method":"Tamoxifen-inducible cardiac-specific conditional knockout mice, I/R injury model, H2O2 compartment-specific measurement, oxygen consumption rate assay, STAT3 dimerization assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — conditional in vivo genetic model with biochemical pathway delineation and functional cardiac phenotype","pmids":["29078279"],"is_preprint":false},{"year":2021,"finding":"GRIM-19 suppresses colorectal cancer cell proliferation and induces apoptosis through posttranslational stabilization of p53: GRIM-19 activates SIRT7, which triggers PCAF-mediated MDM2 ubiquitination, reducing MDM2-dependent p53 degradation.","method":"Overexpression/KD in CRC cells, xenograft model, co-immunoprecipitation, ubiquitination assay, siRNA epistasis","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 — epistasis placing GRIM-19 upstream of SIRT7/PCAF/MDM2/p53 with Co-IP and ubiquitination assays, single lab","pmids":["34461110"],"is_preprint":false},{"year":2010,"finding":"An N-terminal structural motif of GRIM-19 bearing similarity to RNA viral proteins is required for STAT3 interaction and antitumor activity; disruption of specific amino acids in this motif or a clinically observed mutation weakens STAT3 binding and ablates growth suppression.","method":"N-terminal deletion and point mutant analysis, co-immunoprecipitation, reporter gene assay, cell growth assay","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — structure-function mapping with STAT3 interaction and growth readouts, single lab","pmids":["20595633"],"is_preprint":false},{"year":2007,"finding":"HHV-6B U95 protein interacts with GRIM-19 (confirmed by Co-IP and confocal co-localization), and U95 expression induces loss of mitochondrial membrane potential and mitochondrial ultrastructural damage; siRNA knockdown of U95 abrogates the loss of mitochondrial membrane potential.","method":"Yeast two-hybrid, co-immunoprecipitation, confocal immunolocalization, mitochondrial membrane potential assay, RNA interference","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — confirmed interaction with functional mitochondrial consequence, single lab","pmids":["17928352"],"is_preprint":false},{"year":2016,"finding":"NDUFA13/GRIM-19 deficiency in sperm midpiece (shown by immunofluorescence) reduces mitochondrial membrane potential, increases ROS, and increases apoptosis; siRNA knockdown in GC2-spd spermatocyte cells reproduces these effects, linking NDUFA13 to sperm motility.","method":"Immunofluorescence localization, mitochondrial membrane potential assay, ROS measurement, apoptosis assay, siRNA knockdown","journal":"Reproductive biomedicine online","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct localization with functional consequence reproduced by siRNA, single lab","pmids":["27789183"],"is_preprint":false},{"year":2022,"finding":"GRIM-19 is a novel binding partner of Mycobacterium tuberculosis Zmp1 metalloprotease; GRIM-19 knockout (CRISPR) macrophages show loss of mitochondrial ROS generation and NLRP3-dependent caspase-1 activation, demonstrating that GRIM-19 is required for NLRP3 inflammasome activation and IL-1β production during mycobacterial infection.","method":"CRISPR/Cas9 knockout macrophage line, protein interaction assay, mitochondrial ROS assay, caspase-1 activation assay, NLRP3 stimuli (ATP, nigericin), mitochondrial membrane potential assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — clean CRISPR KO with multiple biochemical readouts and epistatic pathway placement, single lab","pmids":["34907600"],"is_preprint":false},{"year":2024,"finding":"GRIM-19 overexpression increases mitochondrial STAT3 levels, induces mitophagy, and alleviates fibrosis in a bleomycin-induced systemic sclerosis model; GRIM-19 recruits STAT3 to mitochondria via the mitochondrial importer Tom20.","method":"GRIM-19 overexpression in SSc mouse model, mitochondrial fractionation, mitophagy assay, fibrosis histology, Tom20 interaction assay","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — in vivo model with mitochondrial biochemistry and novel Tom20 link, single lab","pmids":["39643607"],"is_preprint":false}],"current_model":"NDUFA13/GRIM-19 is an essential accessory subunit of mitochondrial respiratory chain Complex I required for its assembly, stability, and electron transfer activity; it also functions as a specific inhibitor of STAT3 transcriptional activity through direct physical interaction (requiring STAT3-S727 and the GRIM-19 N-terminal motif), acts as a chaperone recruiting STAT3 to the mitochondrial inner membrane via Tom20, mediates electron leak-driven cytosolic H2O2 signaling and NLRP3 inflammasome activation through mitochondrial ROS, and is required for IFN-β/retinoic acid-induced tumor cell death and innate immune responses, with tumor-derived mutations that disrupt STAT3 binding or Complex I maintenance promoting oncogenesis."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing that GRIM-19 is a cell-death effector answered the question of what genes mediate IFN-β/retinoic acid-induced tumor cell killing, positioning it as a novel death regulator before its mitochondrial identity was known.","evidence":"Antisense knockout genetic screen with gain- and loss-of-function validation in tumor cell lines","pmids":["10924506"],"confidence":"High","gaps":["Molecular mechanism of death induction unknown","No mitochondrial connection yet established","Endogenous regulation of GRIM-19 expression uncharacterized"]},{"year":2001,"claim":"Identifying GRIM-19 as a bona fide Complex I subunit resolved the paradox of a death gene being a housekeeping respiratory chain component, unifying its proapoptotic and metabolic functions.","evidence":"Mass spectrometric peptide sequencing of purified bovine Complex I subcomplex Iλ","pmids":["11522775"],"confidence":"High","gaps":["Whether GRIM-19 is required for Complex I assembly versus only structural","How a Complex I subunit participates in cell death signaling"]},{"year":2003,"claim":"Discovery of the direct, selective GRIM-19–STAT3 interaction and its dependence on STAT3-S727 phosphorylation established GRIM-19 as a specific STAT3 inhibitor acting at the transactivation domain level, independent of STAT3 DNA binding or tyrosine phosphorylation.","evidence":"Yeast two-hybrid, reciprocal co-immunoprecipitation, point mutant analysis (S727A), reporter assays in two independent laboratories","pmids":["12628925","12867595"],"confidence":"High","gaps":["Structural basis of the GRIM-19–STAT3 interface unresolved","Whether the interaction occurs in the nucleus, cytoplasm, or mitochondria","Physiological consequence of STAT3 inhibition in non-tumor contexts unknown"]},{"year":2004,"claim":"Knockout mice proved GRIM-19 is essential for Complex I assembly and embryonic viability, demonstrating it is not merely a structural passenger but a required assembly factor whose loss destroys Complex I and affects other respiratory complexes.","evidence":"Homozygous knockout mice lethal at E9.5; native immunoprecipitation and electron transfer activity assays in embryonic cells","pmids":["15367666"],"confidence":"High","gaps":["Step at which GRIM-19 acts in CI assembly pathway undefined","Whether heterozygous loss has phenotypic consequences in specific tissues"]},{"year":2005,"claim":"Identifying the GRIM-19–NOD2 interaction linked mitochondrial Complex I biology to innate immune pattern recognition, showing GRIM-19 is required for NF-κB activation downstream of muramyl dipeptide sensing.","evidence":"Yeast two-hybrid, endogenous co-immunoprecipitation in intestinal epithelial cells, siRNA knockdown with bacterial invasion and NF-κB reporter assays","pmids":["15753091"],"confidence":"Medium","gaps":["Whether the NOD2 interaction is direct or bridged by STAT3","Not replicated by an independent group","Mechanism linking GRIM-19 to NF-κB activation unclear"]},{"year":2007,"claim":"Multiple viral proteins (KSHV vIRF1, HPV E6, HHV-6B U95) were shown to target GRIM-19, establishing it as a convergent viral immune-evasion target whose neutralization disrupts both mitochondrial function and IFN-mediated cell death.","evidence":"Yeast two-hybrid, co-immunoprecipitation, mitochondrial membrane potential and cell death assays across separate viral systems","pmids":["12163600","17928352","17297443"],"confidence":"Medium","gaps":["Structural details of viral protein–GRIM-19 interfaces unknown","In vivo relevance during natural viral infection not demonstrated"]},{"year":2008,"claim":"Domain mapping resolved which GRIM-19 regions are required for mitochondrial localization, membrane potential maintenance, and Complex I incorporation, showing that these are genetically separable functions.","evidence":"Systematic deletion/truncation mutant analysis with mitochondrial membrane potential, Complex I assembly, and apoptosis readouts","pmids":["18287540"],"confidence":"High","gaps":["No high-resolution structure of GRIM-19 within Complex I","How the dominant-negative mutant disrupts ΔΨm while assembled into CI is mechanistically unclear"]},{"year":2010,"claim":"Identification of an N-terminal motif required for STAT3 binding and tumor suppression explained how tumor-derived point mutations selectively abolish the STAT3-inhibitory arm of GRIM-19 without necessarily destroying Complex I function.","evidence":"N-terminal deletion/point mutant analysis with co-immunoprecipitation, reporter, and growth assays","pmids":["20595633","23386605"],"confidence":"Medium","gaps":["Whether tumor mutations also affect Complex I assembly in patient tissues not tested","No crystal structure of the N-terminal motif"]},{"year":2012,"claim":"Demonstrating that GRIM-19 chaperones STAT3 into the mitochondrial inner membrane via Tom20 established a non-transcriptional mitochondrial role for STAT3 dependent on GRIM-19, with S727 phosphorylation gating import efficiency.","evidence":"In vitro mitochondrial import assay, sub-mitochondrial fractionation, co-immunoprecipitation, S727A mutagenesis","pmids":["23271731"],"confidence":"High","gaps":["Whether GRIM-19 directly contacts Tom20 or acts through an adaptor unknown","Stoichiometry of the GRIM-19–STAT3–Tom20 import complex not defined"]},{"year":2012,"claim":"Linking RIPK1-dependent STAT3-S727 phosphorylation to GRIM-19-mediated mitochondrial STAT3 translocation and ROS during necroptosis placed GRIM-19 at the nexus of programmed necrosis and mitochondrial signaling.","evidence":"siRNA knockdown, necrostatin-1 inhibition, phospho-specific immunoblotting, mitochondrial fractionation, ROS measurement","pmids":["22393233"],"confidence":"High","gaps":["Whether GRIM-19 is a RIPK3 substrate or only a passive chaperone unknown","Downstream mechanism by which mitochondrial STAT3 increases ROS not resolved"]},{"year":2013,"claim":"Conditional skin-specific heterozygous GRIM-19 deletion was sufficient to promote carcinogenesis with elevated STAT3 activity and disrupted ETC assembly, providing the first in vivo genetic proof that GRIM-19 haploinsufficiency is tumor-promoting.","evidence":"Conditional knockout mice with chemical carcinogenesis, Complex I assembly, STAT3 activity, and gene expression analysis","pmids":["24145455"],"confidence":"High","gaps":["Whether tumor promotion is driven primarily by STAT3 derepression or ETC dysfunction or both","Applicability to other tissue types unknown"]},{"year":2015,"claim":"Identification of the first germline NDUFA13 mutation in patients with neurological disease and severely reduced Complex I established NDUFA13 as a Mendelian mitochondrial disease gene.","evidence":"Patient mutation identification, BN-PAGE for CI holoenzyme/supercomplexes, enzymatic activity assay, siRNA phenocopy in control cells","pmids":["25901006"],"confidence":"High","gaps":["Only one family reported; allelic spectrum unknown","Whether STAT3 dysregulation contributes to the neurological phenotype not tested"]},{"year":2017,"claim":"Cardiac-specific heterozygous NDUFA13 deletion revealed that partial Complex I deficiency causes site-specific electron leak generating cytosolic (not mitochondrial matrix) H₂O₂, which drives protective STAT3 dimerization during ischemia-reperfusion, providing the first compartment-resolved ROS signaling model for this subunit.","evidence":"Tamoxifen-inducible cardiac conditional knockout, ischemia-reperfusion model, compartment-specific H₂O₂ sensors, STAT3 dimerization assay","pmids":["29078279"],"confidence":"High","gaps":["Precise electron leak site within CI not mapped at atomic resolution","Whether chronic cytosolic H₂O₂ has deleterious long-term cardiac effects unknown"]},{"year":2022,"claim":"CRISPR knockout in macrophages proved GRIM-19 is required for NLRP3 inflammasome activation via mitochondrial ROS, connecting Complex I integrity to innate immune IL-1β production during mycobacterial infection.","evidence":"CRISPR/Cas9 knockout macrophage line, mitochondrial ROS, caspase-1 activation, NLRP3 stimulation with ATP and nigericin","pmids":["34907600"],"confidence":"High","gaps":["Whether GRIM-19 acts upstream of NLRP3 solely through ROS or also through direct protein interaction","Relevance to non-mycobacterial NLRP3 triggers in vivo not fully tested"]},{"year":2024,"claim":"Demonstration that GRIM-19 recruits STAT3 to mitochondria via Tom20 to induce mitophagy and alleviate fibrosis extended GRIM-19's mitochondrial chaperone role to a disease-relevant mitophagy pathway.","evidence":"GRIM-19 overexpression in bleomycin-induced systemic sclerosis mouse model, mitochondrial fractionation, mitophagy assay, Tom20 interaction assay","pmids":["39643607"],"confidence":"Medium","gaps":["Whether mitophagy induction requires STAT3 or is a parallel GRIM-19 function","Tom20 interaction not yet mapped at the residue level","Single-lab finding awaiting independent replication"]},{"year":null,"claim":"A high-resolution structural model of GRIM-19 within the intact human Complex I that explains both its electron-leak site and its STAT3-binding interface remains unavailable, and the mechanism by which partial GRIM-19 loss shifts ROS production to the cytosolic compartment is unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of GRIM-19 with STAT3 or within human CI","Mechanism of selective cytosolic vs. matrix ROS generation not molecularly defined","Relative contributions of STAT3 derepression vs. ETC dysfunction to tumorigenesis not genetically separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,11,15,16,21]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[6,25]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4,5,18]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,4,5,6,19,24]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,4,5,18,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,7,10,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,14,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,16,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,16,18]}],"complexes":["Mitochondrial Complex I (NADH:ubiquinone oxidoreductase)"],"partners":["STAT3","NOD2","HTRA2","E6AP","TOMM20","RIPK1"],"other_free_text":[]},"mechanistic_narrative":"NDUFA13 (GRIM-19) is an essential accessory subunit of mitochondrial respiratory chain Complex I that links oxidative phosphorylation to cell death signaling, STAT3 regulation, and innate immunity. It is required for Complex I assembly, stability, electron transfer activity, and maintenance of mitochondrial membrane potential, with homozygous knockout causing embryonic lethality and germline mutations causing early-onset neurological disease [PMID:15367666, PMID:25901006, PMID:18287540]. NDUFA13 directly binds STAT3 via a phospho-S727-dependent interaction and an N-terminal structural motif, functioning both as an inhibitor of STAT3 nuclear transcriptional activity and as a chaperone that recruits STAT3 to the mitochondrial inner membrane through Tom20; loss of this interaction—including by tumor-derived somatic mutations—derepresses STAT3 signaling and promotes oncogenesis [PMID:12628925, PMID:12867595, PMID:23271731, PMID:24145455, PMID:23386605]. NDUFA13 mediates electron leak-driven cytosolic H₂O₂ production that activates NLRP3 inflammasome-dependent caspase-1/IL-1β responses during infection and cardioprotective STAT3 dimerization during ischemia-reperfusion injury [PMID:29078279, PMID:34907600, PMID:22665480]."},"prefetch_data":{"uniprot":{"accession":"Q9P0J0","full_name":"NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13","aliases":["Cell death regulatory protein GRIM-19","Complex I-B16.6","CI-B16.6","Gene associated with retinoic and interferon-induced mortality 19 protein","GRIM-19","Gene associated with retinoic and IFN-induced mortality 19 protein","NADH-ubiquinone oxidoreductase B16.6 subunit"],"length_aa":144,"mass_kda":16.7,"function":"Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis (PubMed:27626371). Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone (PubMed:27626371). Involved in the interferon/all-trans-retinoic acid (IFN/RA) induced cell death. This apoptotic activity is inhibited by interaction with viral IRF1. Prevents the transactivation of STAT3 target genes. May play a role in CARD15-mediated innate mucosal responses and serve to regulate intestinal epithelial cell responses to microbes (PubMed:15753091)","subcellular_location":"Mitochondrion inner membrane; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9P0J0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NDUFA13","classification":"Not Classified","n_dependent_lines":359,"n_total_lines":1208,"dependency_fraction":0.29718543046357615},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NDUFA13","total_profiled":1310},"omim":[{"mim_id":"618855","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 44; COXPD44","url":"https://www.omim.org/entry/618855"},{"mim_id":"618251","title":"MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 31; 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acids","url":"https://pubmed.ncbi.nlm.nih.gov/21184119","citation_count":8,"is_preprint":false},{"pmid":"25351437","id":"PMC_25351437","title":"GRIM‑19‑mediated Stat3 activation is a determinant for resveratrol‑induced proliferation and cytotoxicity in cervical tumor‑derived cell lines.","date":"2014","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/25351437","citation_count":8,"is_preprint":false},{"pmid":"39643607","id":"PMC_39643607","title":"GRIM-19-mediated induction of mitochondrial STAT3 alleviates systemic sclerosis by inhibiting fibrosis and Th2/Th17 cells.","date":"2024","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39643607","citation_count":7,"is_preprint":false},{"pmid":"39158709","id":"PMC_39158709","title":"SGK3 deficiency in macrophages suppresses angiotensin II-induced cardiac remodeling via regulating Ndufa13-mediated mitochondrial oxidative stress.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39158709","citation_count":7,"is_preprint":false},{"pmid":"25955394","id":"PMC_25955394","title":"Upregulation of GRIM-19 inhibits the growth and invasion of human breast cancer cells.","date":"2015","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/25955394","citation_count":7,"is_preprint":false},{"pmid":"32896475","id":"PMC_32896475","title":"Interaction of M2 macrophages and endometrial cells induces downregulation of GRIM-19 in endometria of adenomyosis.","date":"2020","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/32896475","citation_count":7,"is_preprint":false},{"pmid":"26458285","id":"PMC_26458285","title":"Enhanced antitumor effect of cisplatin in human oral squamous cell carcinoma cells by tumor suppressor GRIM‑19.","date":"2015","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/26458285","citation_count":7,"is_preprint":false},{"pmid":"34848745","id":"PMC_34848745","title":"Structural exploration with AlphaFold2-generated STAT3α structure reveals selective elements in STAT3α-GRIM-19 interactions involved in negative regulation.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34848745","citation_count":7,"is_preprint":false},{"pmid":"26011333","id":"PMC_26011333","title":"Expression of GW112 and GRIM-19 in colorectal cancer tissues.","date":"2015","source":"Journal of B.U.ON. : official journal of the Balkan Union of Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26011333","citation_count":7,"is_preprint":false},{"pmid":"38974954","id":"PMC_38974954","title":"Mitochondrial GRIM19 Loss Induces Liver Fibrosis through NLRP3/IL33 Activation via Reactive Oxygen Species/NF-кB Signaling.","date":"2024","source":"Journal of clinical and translational hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/38974954","citation_count":7,"is_preprint":false},{"pmid":"23851499","id":"PMC_23851499","title":"GRIM-19 mutations fail to inhibit v-Src-induced oncogenesis.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23851499","citation_count":7,"is_preprint":false},{"pmid":"19622307","id":"PMC_19622307","title":"[Expression and clinical significance of GRIM-19 in non-small cell lung cancer].","date":"2009","source":"Ai zheng = Aizheng = Chinese journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19622307","citation_count":7,"is_preprint":false},{"pmid":"25174621","id":"PMC_25174621","title":"Upregulation of GRIM-19 suppresses the growth of oral squamous cell carcinoma in vitro and in vivo.","date":"2014","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/25174621","citation_count":7,"is_preprint":false},{"pmid":"23178692","id":"PMC_23178692","title":"Expression and functional characterization of a gene associated with retinoid-interferon-induced mortality 19 (GRIM-19) from orange-spotted grouper (Epinephelus coioides).","date":"2012","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23178692","citation_count":7,"is_preprint":false},{"pmid":"33163248","id":"PMC_33163248","title":"GRIM-19 Ameliorates Multiple Sclerosis in a Mouse Model of Experimental Autoimmune Encephalomyelitis with Reciprocal Regulation of IFNγ/Th1 and IL-17A/Th17 Cells.","date":"2020","source":"Immune network","url":"https://pubmed.ncbi.nlm.nih.gov/33163248","citation_count":6,"is_preprint":false},{"pmid":"29074558","id":"PMC_29074558","title":"miR-6743-5p, as a direct upstream regulator of GRIM-19, enhances proliferation and suppresses apoptosis in glioma cells.","date":"2017","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/29074558","citation_count":6,"is_preprint":false},{"pmid":"37118800","id":"PMC_37118800","title":"LncRNA SATB2-AS1 overexpression represses the development of hepatocellular carcinoma through regulating the miR-3678-3p/GRIM-19 axis.","date":"2023","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/37118800","citation_count":6,"is_preprint":false},{"pmid":"29306209","id":"PMC_29306209","title":"Retinoid interferon-induced mortality19 (GRIM19) inhibits proliferation and invasion in rheumatoid arthritis fibroblast-like synoviocytes.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/29306209","citation_count":5,"is_preprint":false},{"pmid":"31531888","id":"PMC_31531888","title":"Upregulation of GRIM-19 augments the sensitivity of prostate cancer cells to docetaxel by targeting Rad23b.","date":"2019","source":"Clinical and experimental pharmacology & physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31531888","citation_count":5,"is_preprint":false},{"pmid":"33509753","id":"PMC_33509753","title":"[Pathogenic role of NDUFA13 inactivation in spontaneous hepatitis in mice and the mechanism].","date":"2021","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/33509753","citation_count":5,"is_preprint":false},{"pmid":"21351527","id":"PMC_21351527","title":"[Expressions of survivin and GRIM-19 in prostate cancer].","date":"2011","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/21351527","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51798,"output_tokens":5823,"usd":0.12137},"stage2":{"model":"claude-opus-4-6","input_tokens":9491,"output_tokens":3829,"usd":0.21477},"total_usd":0.33614,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"GRIM-19/NDUFA13 is a bona fide subunit of bovine mitochondrial NADH:ubiquinone oxidoreductase (Complex I), identified by mass-spectrometric peptide sequencing of subcomplex Iλ (hydrophilic arm), with the N-terminus shown to be acetylated.\",\n      \"method\": \"Denaturing gel electrophoresis of Complex I subcomplex, tryptic digestion, mass spectrometry, cDNA cloning, intact protein mass measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical identification from purified complex with MS and sequencing\",\n      \"pmids\": [\"11522775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"GRIM-19 is induced by the IFN-β/retinoic acid combination and is required for IFN/RA-induced tumor cell death; antisense inactivation of GRIM-19 confers resistance to cell death and overexpression enhances it.\",\n      \"method\": \"Antisense knockout genetic screen, overexpression and antisense expression assays in tumor cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original genetic screen with loss- and gain-of-function validation, foundational paper\",\n      \"pmids\": [\"10924506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GRIM-19 physically interacts with STAT3 (but not STAT1 or STAT5a), co-localizes with STAT3 at perinuclear mitochondrial aggregates, inhibits STAT3 nuclear translocation stimulated by EGF, and represses STAT3 transcriptional activity and target gene expression.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, co-localization with mitochondrial markers, domain mapping, reporter assays, growth suppression assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction confirmed, multiple orthogonal methods in one study, replicated by independent lab (PMID:12867595)\",\n      \"pmids\": [\"12628925\", \"12867595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GRIM-19 binds specifically to STAT3 (not STAT1) via the STAT3 transactivation domain; residue S727 of STAT3 is required for GRIM-19 binding. GRIM-19 inhibits STAT3-driven transcription without blocking STAT3 tyrosine phosphorylation or DNA binding.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, point mutant analysis, reporter gene assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis defining binding residue, orthogonal interaction assays\",\n      \"pmids\": [\"12867595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GRIM-19 is essential for Complex I assembly and electron transfer activity; homozygous knockout in mice causes embryonic lethality at E9.5 with abnormal mitochondrial structure and distribution, and loss of GRIM-19 destroys Complex I assembly and influences other respiratory chain complexes.\",\n      \"method\": \"Gene targeting/knockout mice, native Complex I immunoprecipitation, electron transfer activity assay, mitochondrial morphology analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean knockout with defined cellular and biochemical phenotypes, replicated in subsequent studies\",\n      \"pmids\": [\"15367666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Functional domain mapping shows that the mitochondrial localization sequence of GRIM-19 is at its N-terminus; deletion of residues 70–80, 90–100, or the C-terminal region (70–144) abolishes mitochondrial transmembrane potential (ΔΨm); deletion of the last 10 C-terminal residues prevents assembly into Complex I; a dominant-negative mutant assembled into Complex I but failed to maintain ΔΨm and sensitized cells to apoptosis.\",\n      \"method\": \"Deletion/truncation/point mutant analysis, mitochondrial membrane potential assay, Complex I assembly assay, apoptosis assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-function mutagenesis with multiple orthogonal functional readouts\",\n      \"pmids\": [\"18287540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GRIM-19 acts as a chaperone to recruit STAT3 into the inner mitochondrial membrane and enhances STAT3 integration into Complex I; the STAT3 S727A mutation reduces import and Complex I assembly even in the presence of GRIM-19.\",\n      \"method\": \"In vitro mitochondrial import assay, sub-mitochondrial fractionation, co-immunoprecipitation, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro import reconstitution with mutagenesis validation\",\n      \"pmids\": [\"23271731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"During TNF-induced necroptosis, RIPK1-dependent phosphorylation of STAT3 on S727 induces its interaction with GRIM-19, leading to mitochondrial translocation of STAT3, increased mitochondrial ROS production, and cell death.\",\n      \"method\": \"siRNA knockdown of RIPK1, necrostatin-1 inhibition, phospho-specific immunoblotting, co-immunoprecipitation, mitochondrial fractionation, ROS measurement\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with RIPK1, reciprocal Co-IP, mitochondrial fractionation, multiple orthogonal methods\",\n      \"pmids\": [\"22393233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"KSHV vIRF1 directly interacts with GRIM-19 via its N-terminal region, co-localizes with GRIM-19, deregulates GRIM-19-induced apoptosis, and inhibits IFN/RA-induced cell death; HPV16 E6 also binds GRIM-19.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation (in vivo and in vitro), confocal co-localization, cell death assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal in vivo/in vitro interaction with functional cell death readout, single lab\",\n      \"pmids\": [\"12163600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"GRIM-19 interacts with NOD2 in intestinal epithelial cells and is required for NF-κB activation following NOD2-mediated recognition of muramyl dipeptide and for control of pathogen invasion.\",\n      \"method\": \"Yeast two-hybrid, endogenous co-immunoprecipitation in HT29 cells, siRNA knockdown, bacterial invasion assay, NF-κB reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — endogenous Co-IP with functional knockdown phenotype, single lab\",\n      \"pmids\": [\"15753091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GRIM-19 physically interacts with the serine protease HtrA2, augments HtrA2-driven destruction of XIAP in an IFN/RA-dependent manner, and promotes cell death; vIRF1 disrupts this interaction to confer resistance to IFN/RA-induced death.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, cell death assay, XIAP degradation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction with functional consequence, single lab\",\n      \"pmids\": [\"17297443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GRIM-19 suppresses v-Src-induced cellular transformation and metastasis by inhibiting STAT3-dependent gene expression and by suppressing tyrosyl phosphorylation of focal adhesion kinase, paxillin, E-cadherin, and γ-catenin independently of STAT3.\",\n      \"method\": \"Overexpression and shRNA knockdown, in vitro transformation assay, in vivo metastasis assay, phospho-Western blotting\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss- and gain-of-function with in vivo validation, two distinct mechanisms identified\",\n      \"pmids\": [\"17823279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GRIM-19 inhibits v-Src-induced cell motility and podosome formation through its N-terminal domain, independently of STAT3; tumor-associated GRIM-19 mutations disrupt this activity and fail to upregulate the lipid raft-associated Src inhibitor Pag1.\",\n      \"method\": \"N-terminal deletion and point mutant analysis, podosome formation assay, cell motility assay, in vivo metastasis assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structure-function with in vivo metastasis readout, single lab\",\n      \"pmids\": [\"19151760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GRIM-19 disrupts the HPV18 E6/E6AP complex by interacting with both E6 and E6AP via its N-terminus, promotes E6AP ubiquitination and degradation, and thereby rescues p53 from degradation and promotes apoptosis in cervical cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, competition pull-down assay, in vivo and in vitro ubiquitination assay, xenograft tumor model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical assays (pull-down, ubiquitination) with in vivo validation, single lab\",\n      \"pmids\": [\"21765936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Heterozygous GRIM-19 knockout macrophages have compromised Complex I activity and elevated ROS, leading to decreased intracellular bacterial killing and reduced proinflammatory cytokine production; bacterial infection normally upregulates GRIM-19 and Complex I activity in wild-type macrophages.\",\n      \"method\": \"Heterozygous knockout mice, Complex I activity assay, ROS measurement, intracellular bacterial killing assay, cytokine ELISA, in vivo infection model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic model with multiple biochemical and functional readouts\",\n      \"pmids\": [\"22665480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tumor-derived somatic mutations in GRIM-19 (L71P, L91P, A95T) cause loss of STAT3 binding, loss of suppression of STAT3 transcriptional activity, and failure to suppress cellular transformation and metastasis in vitro and in vivo.\",\n      \"method\": \"Somatic mutation screening of primary tumors, co-immunoprecipitation, transformation assay, in vivo tumor growth and metastasis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structure-function with tumor-derived mutations, in vivo validation, single lab\",\n      \"pmids\": [\"23386605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Monoallelic skin-specific deletion of GRIM-19 is sufficient to promote chemical carcinogenesis and invasive squamous cell carcinoma, associated with high STAT3 activity, upregulated STAT3-responsive genes, mitochondrial electron transport dysfunction, and failure to assemble ETC complexes.\",\n      \"method\": \"Conditional knockout mice, chemical carcinogenesis protocol, Complex I assembly assay, STAT3 activity assay, gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo conditional KO with defined molecular and biochemical phenotypes\",\n      \"pmids\": [\"24145455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GRIM-19 opposes the Warburg effect in glioblastoma by destabilizing HIF-1α: GRIM-19 loss promotes STAT3-dependent HIF-1α synthesis and prevents pVHL-mediated HIF-1α ubiquitination/proteasomal degradation.\",\n      \"method\": \"Overexpression/knockdown in glioblastoma cell lines, HIF-1α protein stability assays, pVHL interaction assay, STAT3 inhibitor\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pathway placement via loss-of-function with mechanistic follow-up, single lab\",\n      \"pmids\": [\"23580587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The first germline pathogenic mutation in NDUFA13/GRIM-19 is identified in patients with early onset hypotonia, dyskinesia, and optic neuropathy; patient cells show drastically reduced Complex I enzymatic activity, reduced CI-driven respiration, and loss of NDUFA13 protein, CI holoenzyme, and supercomplexes; NDUFA13 silencing in control cells reproduces CI instability.\",\n      \"method\": \"Patient mutation identification, biochemical analysis of muscle biopsies and fibroblasts, BN-PAGE for Complex I holoenzyme and supercomplexes, Western blot, siRNA knockdown\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — patient genetics with biochemical reconstitution of phenotype by siRNA, multiple orthogonal assays\",\n      \"pmids\": [\"25901006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cardiac-specific heterozygous NDUFA13 knockout mice show basal-state cytosolic H2O2 elevation (not mitochondrial), which drives STAT3 dimerization and antiapoptotic signaling, reducing infarct size during ischemia-reperfusion injury; NDUFA13 is positioned near low-electrochemical-potential subunits of Complex I and mediates electron leak.\",\n      \"method\": \"Tamoxifen-inducible cardiac-specific conditional knockout mice, I/R injury model, H2O2 compartment-specific measurement, oxygen consumption rate assay, STAT3 dimerization assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional in vivo genetic model with biochemical pathway delineation and functional cardiac phenotype\",\n      \"pmids\": [\"29078279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GRIM-19 suppresses colorectal cancer cell proliferation and induces apoptosis through posttranslational stabilization of p53: GRIM-19 activates SIRT7, which triggers PCAF-mediated MDM2 ubiquitination, reducing MDM2-dependent p53 degradation.\",\n      \"method\": \"Overexpression/KD in CRC cells, xenograft model, co-immunoprecipitation, ubiquitination assay, siRNA epistasis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — epistasis placing GRIM-19 upstream of SIRT7/PCAF/MDM2/p53 with Co-IP and ubiquitination assays, single lab\",\n      \"pmids\": [\"34461110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"An N-terminal structural motif of GRIM-19 bearing similarity to RNA viral proteins is required for STAT3 interaction and antitumor activity; disruption of specific amino acids in this motif or a clinically observed mutation weakens STAT3 binding and ablates growth suppression.\",\n      \"method\": \"N-terminal deletion and point mutant analysis, co-immunoprecipitation, reporter gene assay, cell growth assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structure-function mapping with STAT3 interaction and growth readouts, single lab\",\n      \"pmids\": [\"20595633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HHV-6B U95 protein interacts with GRIM-19 (confirmed by Co-IP and confocal co-localization), and U95 expression induces loss of mitochondrial membrane potential and mitochondrial ultrastructural damage; siRNA knockdown of U95 abrogates the loss of mitochondrial membrane potential.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, confocal immunolocalization, mitochondrial membrane potential assay, RNA interference\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — confirmed interaction with functional mitochondrial consequence, single lab\",\n      \"pmids\": [\"17928352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NDUFA13/GRIM-19 deficiency in sperm midpiece (shown by immunofluorescence) reduces mitochondrial membrane potential, increases ROS, and increases apoptosis; siRNA knockdown in GC2-spd spermatocyte cells reproduces these effects, linking NDUFA13 to sperm motility.\",\n      \"method\": \"Immunofluorescence localization, mitochondrial membrane potential assay, ROS measurement, apoptosis assay, siRNA knockdown\",\n      \"journal\": \"Reproductive biomedicine online\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct localization with functional consequence reproduced by siRNA, single lab\",\n      \"pmids\": [\"27789183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GRIM-19 is a novel binding partner of Mycobacterium tuberculosis Zmp1 metalloprotease; GRIM-19 knockout (CRISPR) macrophages show loss of mitochondrial ROS generation and NLRP3-dependent caspase-1 activation, demonstrating that GRIM-19 is required for NLRP3 inflammasome activation and IL-1β production during mycobacterial infection.\",\n      \"method\": \"CRISPR/Cas9 knockout macrophage line, protein interaction assay, mitochondrial ROS assay, caspase-1 activation assay, NLRP3 stimuli (ATP, nigericin), mitochondrial membrane potential assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean CRISPR KO with multiple biochemical readouts and epistatic pathway placement, single lab\",\n      \"pmids\": [\"34907600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GRIM-19 overexpression increases mitochondrial STAT3 levels, induces mitophagy, and alleviates fibrosis in a bleomycin-induced systemic sclerosis model; GRIM-19 recruits STAT3 to mitochondria via the mitochondrial importer Tom20.\",\n      \"method\": \"GRIM-19 overexpression in SSc mouse model, mitochondrial fractionation, mitophagy assay, fibrosis histology, Tom20 interaction assay\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — in vivo model with mitochondrial biochemistry and novel Tom20 link, single lab\",\n      \"pmids\": [\"39643607\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NDUFA13/GRIM-19 is an essential accessory subunit of mitochondrial respiratory chain Complex I required for its assembly, stability, and electron transfer activity; it also functions as a specific inhibitor of STAT3 transcriptional activity through direct physical interaction (requiring STAT3-S727 and the GRIM-19 N-terminal motif), acts as a chaperone recruiting STAT3 to the mitochondrial inner membrane via Tom20, mediates electron leak-driven cytosolic H2O2 signaling and NLRP3 inflammasome activation through mitochondrial ROS, and is required for IFN-β/retinoic acid-induced tumor cell death and innate immune responses, with tumor-derived mutations that disrupt STAT3 binding or Complex I maintenance promoting oncogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NDUFA13 (GRIM-19) is an essential accessory subunit of mitochondrial respiratory chain Complex I that links oxidative phosphorylation to cell death signaling, STAT3 regulation, and innate immunity. It is required for Complex I assembly, stability, electron transfer activity, and maintenance of mitochondrial membrane potential, with homozygous knockout causing embryonic lethality and germline mutations causing early-onset neurological disease [PMID:15367666, PMID:25901006, PMID:18287540]. NDUFA13 directly binds STAT3 via a phospho-S727-dependent interaction and an N-terminal structural motif, functioning both as an inhibitor of STAT3 nuclear transcriptional activity and as a chaperone that recruits STAT3 to the mitochondrial inner membrane through Tom20; loss of this interaction—including by tumor-derived somatic mutations—derepresses STAT3 signaling and promotes oncogenesis [PMID:12628925, PMID:12867595, PMID:23271731, PMID:24145455, PMID:23386605]. NDUFA13 mediates electron leak-driven cytosolic H₂O₂ production that activates NLRP3 inflammasome-dependent caspase-1/IL-1β responses during infection and cardioprotective STAT3 dimerization during ischemia-reperfusion injury [PMID:29078279, PMID:34907600, PMID:22665480].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that GRIM-19 is a cell-death effector answered the question of what genes mediate IFN-β/retinoic acid-induced tumor cell killing, positioning it as a novel death regulator before its mitochondrial identity was known.\",\n      \"evidence\": \"Antisense knockout genetic screen with gain- and loss-of-function validation in tumor cell lines\",\n      \"pmids\": [\"10924506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of death induction unknown\", \"No mitochondrial connection yet established\", \"Endogenous regulation of GRIM-19 expression uncharacterized\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying GRIM-19 as a bona fide Complex I subunit resolved the paradox of a death gene being a housekeeping respiratory chain component, unifying its proapoptotic and metabolic functions.\",\n      \"evidence\": \"Mass spectrometric peptide sequencing of purified bovine Complex I subcomplex Iλ\",\n      \"pmids\": [\"11522775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GRIM-19 is required for Complex I assembly versus only structural\", \"How a Complex I subunit participates in cell death signaling\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery of the direct, selective GRIM-19–STAT3 interaction and its dependence on STAT3-S727 phosphorylation established GRIM-19 as a specific STAT3 inhibitor acting at the transactivation domain level, independent of STAT3 DNA binding or tyrosine phosphorylation.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-immunoprecipitation, point mutant analysis (S727A), reporter assays in two independent laboratories\",\n      \"pmids\": [\"12628925\", \"12867595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the GRIM-19–STAT3 interface unresolved\", \"Whether the interaction occurs in the nucleus, cytoplasm, or mitochondria\", \"Physiological consequence of STAT3 inhibition in non-tumor contexts unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Knockout mice proved GRIM-19 is essential for Complex I assembly and embryonic viability, demonstrating it is not merely a structural passenger but a required assembly factor whose loss destroys Complex I and affects other respiratory complexes.\",\n      \"evidence\": \"Homozygous knockout mice lethal at E9.5; native immunoprecipitation and electron transfer activity assays in embryonic cells\",\n      \"pmids\": [\"15367666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Step at which GRIM-19 acts in CI assembly pathway undefined\", \"Whether heterozygous loss has phenotypic consequences in specific tissues\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying the GRIM-19–NOD2 interaction linked mitochondrial Complex I biology to innate immune pattern recognition, showing GRIM-19 is required for NF-κB activation downstream of muramyl dipeptide sensing.\",\n      \"evidence\": \"Yeast two-hybrid, endogenous co-immunoprecipitation in intestinal epithelial cells, siRNA knockdown with bacterial invasion and NF-κB reporter assays\",\n      \"pmids\": [\"15753091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the NOD2 interaction is direct or bridged by STAT3\", \"Not replicated by an independent group\", \"Mechanism linking GRIM-19 to NF-κB activation unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Multiple viral proteins (KSHV vIRF1, HPV E6, HHV-6B U95) were shown to target GRIM-19, establishing it as a convergent viral immune-evasion target whose neutralization disrupts both mitochondrial function and IFN-mediated cell death.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, mitochondrial membrane potential and cell death assays across separate viral systems\",\n      \"pmids\": [\"12163600\", \"17928352\", \"17297443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural details of viral protein–GRIM-19 interfaces unknown\", \"In vivo relevance during natural viral infection not demonstrated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Domain mapping resolved which GRIM-19 regions are required for mitochondrial localization, membrane potential maintenance, and Complex I incorporation, showing that these are genetically separable functions.\",\n      \"evidence\": \"Systematic deletion/truncation mutant analysis with mitochondrial membrane potential, Complex I assembly, and apoptosis readouts\",\n      \"pmids\": [\"18287540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of GRIM-19 within Complex I\", \"How the dominant-negative mutant disrupts ΔΨm while assembled into CI is mechanistically unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of an N-terminal motif required for STAT3 binding and tumor suppression explained how tumor-derived point mutations selectively abolish the STAT3-inhibitory arm of GRIM-19 without necessarily destroying Complex I function.\",\n      \"evidence\": \"N-terminal deletion/point mutant analysis with co-immunoprecipitation, reporter, and growth assays\",\n      \"pmids\": [\"20595633\", \"23386605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether tumor mutations also affect Complex I assembly in patient tissues not tested\", \"No crystal structure of the N-terminal motif\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that GRIM-19 chaperones STAT3 into the mitochondrial inner membrane via Tom20 established a non-transcriptional mitochondrial role for STAT3 dependent on GRIM-19, with S727 phosphorylation gating import efficiency.\",\n      \"evidence\": \"In vitro mitochondrial import assay, sub-mitochondrial fractionation, co-immunoprecipitation, S727A mutagenesis\",\n      \"pmids\": [\"23271731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GRIM-19 directly contacts Tom20 or acts through an adaptor unknown\", \"Stoichiometry of the GRIM-19–STAT3–Tom20 import complex not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linking RIPK1-dependent STAT3-S727 phosphorylation to GRIM-19-mediated mitochondrial STAT3 translocation and ROS during necroptosis placed GRIM-19 at the nexus of programmed necrosis and mitochondrial signaling.\",\n      \"evidence\": \"siRNA knockdown, necrostatin-1 inhibition, phospho-specific immunoblotting, mitochondrial fractionation, ROS measurement\",\n      \"pmids\": [\"22393233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GRIM-19 is a RIPK3 substrate or only a passive chaperone unknown\", \"Downstream mechanism by which mitochondrial STAT3 increases ROS not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Conditional skin-specific heterozygous GRIM-19 deletion was sufficient to promote carcinogenesis with elevated STAT3 activity and disrupted ETC assembly, providing the first in vivo genetic proof that GRIM-19 haploinsufficiency is tumor-promoting.\",\n      \"evidence\": \"Conditional knockout mice with chemical carcinogenesis, Complex I assembly, STAT3 activity, and gene expression analysis\",\n      \"pmids\": [\"24145455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether tumor promotion is driven primarily by STAT3 derepression or ETC dysfunction or both\", \"Applicability to other tissue types unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of the first germline NDUFA13 mutation in patients with neurological disease and severely reduced Complex I established NDUFA13 as a Mendelian mitochondrial disease gene.\",\n      \"evidence\": \"Patient mutation identification, BN-PAGE for CI holoenzyme/supercomplexes, enzymatic activity assay, siRNA phenocopy in control cells\",\n      \"pmids\": [\"25901006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Only one family reported; allelic spectrum unknown\", \"Whether STAT3 dysregulation contributes to the neurological phenotype not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Cardiac-specific heterozygous NDUFA13 deletion revealed that partial Complex I deficiency causes site-specific electron leak generating cytosolic (not mitochondrial matrix) H₂O₂, which drives protective STAT3 dimerization during ischemia-reperfusion, providing the first compartment-resolved ROS signaling model for this subunit.\",\n      \"evidence\": \"Tamoxifen-inducible cardiac conditional knockout, ischemia-reperfusion model, compartment-specific H₂O₂ sensors, STAT3 dimerization assay\",\n      \"pmids\": [\"29078279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise electron leak site within CI not mapped at atomic resolution\", \"Whether chronic cytosolic H₂O₂ has deleterious long-term cardiac effects unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CRISPR knockout in macrophages proved GRIM-19 is required for NLRP3 inflammasome activation via mitochondrial ROS, connecting Complex I integrity to innate immune IL-1β production during mycobacterial infection.\",\n      \"evidence\": \"CRISPR/Cas9 knockout macrophage line, mitochondrial ROS, caspase-1 activation, NLRP3 stimulation with ATP and nigericin\",\n      \"pmids\": [\"34907600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GRIM-19 acts upstream of NLRP3 solely through ROS or also through direct protein interaction\", \"Relevance to non-mycobacterial NLRP3 triggers in vivo not fully tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that GRIM-19 recruits STAT3 to mitochondria via Tom20 to induce mitophagy and alleviate fibrosis extended GRIM-19's mitochondrial chaperone role to a disease-relevant mitophagy pathway.\",\n      \"evidence\": \"GRIM-19 overexpression in bleomycin-induced systemic sclerosis mouse model, mitochondrial fractionation, mitophagy assay, Tom20 interaction assay\",\n      \"pmids\": [\"39643607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mitophagy induction requires STAT3 or is a parallel GRIM-19 function\", \"Tom20 interaction not yet mapped at the residue level\", \"Single-lab finding awaiting independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structural model of GRIM-19 within the intact human Complex I that explains both its electron-leak site and its STAT3-binding interface remains unavailable, and the mechanism by which partial GRIM-19 loss shifts ROS production to the cytosolic compartment is unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution structure of GRIM-19 with STAT3 or within human CI\", \"Mechanism of selective cytosolic vs. matrix ROS generation not molecularly defined\", \"Relative contributions of STAT3 derepression vs. ETC dysfunction to tumorigenesis not genetically separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 11, 15, 16, 21]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [6, 25]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4, 5, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 4, 5, 6, 19, 24]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 4, 5, 18, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 7, 10, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 14, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 16, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 16, 18]}\n    ],\n    \"complexes\": [\n      \"Mitochondrial Complex I (NADH:ubiquinone oxidoreductase)\"\n    ],\n    \"partners\": [\n      \"STAT3\",\n      \"NOD2\",\n      \"HTRA2\",\n      \"E6AP\",\n      \"TOMM20\",\n      \"RIPK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}