{"gene":"OGDH","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1989,"finding":"KGD1 (yeast ortholog of OGDH) encodes the alpha-ketoglutarate dehydrogenase (E1) component of the alpha-ketoglutarate dehydrogenase complex; disruption of the chromosomal copy causes deficiency in alpha-ketoglutarate dehydrogenase activity, and the gene is catabolite repressed via HAP2/HAP3 regulatory proteins binding to a promoter element between -354 and -143.","method":"Gene cloning by complementation of kgd1 mutants, chromosomal disruption (kgd1::URA3), lacZ fusion reporter assays, testing in hap2/hap3 mutant backgrounds","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic disruption with defined enzymatic phenotype, promoter mapping with reporter assays, and regulatory epistasis via hap2/hap3 mutants in a single rigorous study","pmids":["2503710"],"is_preprint":false},{"year":1993,"finding":"The ogd1 and kgd1 mutations in yeast, both abolishing 2-oxoglutarate dehydrogenase activity, are allelic (same gene locus), as demonstrated by complementation and meiotic mapping.","method":"Complementation assay, allelism test, meiotic mapping","journal":"Current genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic complementation and meiotic mapping from a single study with two orthogonal methods","pmids":["8299151"],"is_preprint":false},{"year":1994,"finding":"The OGDH gene (encoding E1k, the E1 subunit of alpha-ketoglutarate dehydrogenase complex) was mapped to human chromosome 7p13-p11.2; a second related sequence (possibly a pseudogene) was mapped to chromosome 10.","method":"Somatic cell hybrid panel mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal localization using somatic cell hybrids, single lab","pmids":["8020988"],"is_preprint":false},{"year":2014,"finding":"OGDH protein undergoes tyrosine/tryptophan nitration in myocardial tissue, and the degree of nitration is higher in diabetic mice compared to controls, indicating that OGDH is subject to oxidative post-translational modification (nitration) that is elevated under diabetic conditions.","method":"Targeted proteomics using parallel reaction monitoring (PRM) and selected reaction monitoring (SRM) mass spectrometry via Skyline-designed methods","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — targeted MS-based identification of nitration sites with relative quantitation, single lab, single method","pmids":["25251478"],"is_preprint":false},{"year":2016,"finding":"OGDH (E1 subunit of the alpha-ketoglutarate dehydrogenase complex) is required for cancer cell proliferation in 3D culture and xenograft tumor growth in a subset of cancer cells that rely on the malate-aspartate shuttle; differential aspartate utilization predicts OGDH dependency.","method":"siRNA screen of TCA cycle enzymes, integrative metabolomics, 3D proliferation assays, xenograft tumor growth assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown with defined metabolic and proliferative phenotypes, multiple orthogonal methods (metabolomics + 3D + xenograft), single lab","pmids":["27732861"],"is_preprint":false},{"year":2019,"finding":"SIRT5 directly interacts with OGDH and desuccinylates OGDH, which inhibits OGDH complex activity; OGDH inhibition (by succinyl phosphonate or siRNA) suppresses cell growth and migration induced by SIRT5 deletion, placing OGDH downstream of SIRT5 in gastric cancer cell proliferation and migration.","method":"Co-immunoprecipitation, siRNA knockdown, succinyl phosphonate inhibitor treatment, cell growth/migration assays, measurement of mitochondrial membrane potential, ATP, ROS, and NADP+/NADPH ratio","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP establishing direct interaction, genetic/pharmacological epistasis placing OGDH downstream of SIRT5, multiple metabolic readouts, single lab with multiple orthogonal methods","pmids":["31247190"],"is_preprint":false},{"year":2019,"finding":"OGDH knockdown in gastric cancer cells decreases mitochondrial membrane potential, oxygen consumption rate, ATP production, and increases ROS and NADP+/NADPH ratio; OGDH overexpression has opposite effects; furthermore, OGDH knockdown reduces Wnt/β-catenin pathway components (β-catenin, slug, TCF8/ZEB1, cyclin D1, MMP9) while overexpression activates this pathway.","method":"siRNA knockdown, overexpression, OCR measurement, ATP assay, ROS measurement, Western blotting for EMT and Wnt pathway markers, xenograft tumor model","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — loss- and gain-of-function with multiple metabolic and signaling readouts, single lab","pmids":["31686854"],"is_preprint":false},{"year":2020,"finding":"OGDH interacts with DHTKD1, dihydrolipoyl succinyltransferase (DLST), and dihydrolipoamide dehydrogenase (DLD) to form a hybrid 2-oxoglutaric and 2-oxoadipic acid dehydrogenase complex; OGDH can use 2-oxoadipic acid as a substrate (in addition to 2-oxoglutarate), contributing to glutaryl-CoA production in cells lacking DHTKD1.","method":"Co-immunoprecipitation, mass spectrometry, HEK-293 cell genetic models (DHTKD1 KO + GCDH KO), metabolite quantification (glutarylcarnitine)","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP establishing complex composition, genetic cell models with metabolite readouts, multiple orthogonal methods in a single rigorous study","pmids":["32160276"],"is_preprint":false},{"year":2020,"finding":"Biallelic loss-of-function variants in OGDH (p.N320S) reduce OGDH protein levels and enzymatic activity in patient fibroblasts and HEK293 cells; expression of mutant OGDH fails to rescue developmental lethality and locomotion defects caused by loss of Drosophila Ogdh, establishing that these variants cause severe loss of OGDH protein function.","method":"Whole exome sequencing, patient fibroblast enzymatic assay, HEK293 transfection with WT vs mutant cDNA, Drosophila rescue experiments (lethality and locomotion assays)","journal":"Journal of inherited metabolic disease","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — enzymatic activity measurements in patient cells, protein quantification, and cross-species functional rescue experiments with multiple orthogonal methods","pmids":["32383294"],"is_preprint":false},{"year":2018,"finding":"OGDH activity regulates intracellular alpha-ketoglutarate (αKG) levels; OGDH knockdown increases endogenous αKG levels and rescues cells from p53 activator Nutlin-3a-induced apoptosis by restoring autophagy and ATG gene expression, placing OGDH downstream of p53 in the regulation of αKG-dependent autophagy and apoptosis.","method":"OGDH siRNA knockdown, cell-permeable αKG analog (DMKG) add-back, autophagy assays, ATG gene expression analysis in Nutlin-3a-treated cells","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — loss-of-function with metabolite add-back rescue, multiple pathway readouts, single lab","pmids":["30289354"],"is_preprint":false},{"year":2022,"finding":"Novel homozygous missense variants in OGDH (p.Pro189Leu and p.Ser297Tyr) cause accelerated protein degradation and reduced protein levels; expression in HEK293 cells shows lower protein levels than WT, and neither variant rescues developmental lethality of Drosophila Ogdh null mutants, confirming these are loss-of-function variants.","method":"Exome sequencing, in silico homology modeling, protein stability assays in patient fibroblasts and HEK293 cells, Drosophila rescue experiments, mini-gene splicing assay for a splice-site variant","journal":"Genetics in medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (protein quantification, splice assay, Drosophila rescue) across independent patient-derived and cell-line models","pmids":["36520152"],"is_preprint":false},{"year":2022,"finding":"OGDH knockdown in human embryonic stem cells (hESCs) via inducible CRISPRi disrupts the TCA cycle, diminishes mitochondrial respiration activity, reduces total ATP levels, and leads to cell death and aberrant transcriptional programs, establishing OGDH as essential for mitochondrial respiration and identity maintenance in primed hESCs.","method":"CRISPRi-mediated knockdown, metabolic flux analysis, ATP measurement, RNA-seq transcriptomics, pharmacological ETC inhibition for comparison","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible genetic loss-of-function with multiple metabolic readouts and transcriptomic profiling, single lab","pmids":["35500439"],"is_preprint":false},{"year":2023,"finding":"CSFV C protein interacts with OGDH protein; CSFV uses autophagy receptors NDP52/NBR1 to target OGDH for degradation via the autophagy-lysosome pathway, reducing OGDH levels and promoting α-KG secretion; OGDH overexpression inhibits CSFV proliferation through modulation of the AMPK-mTOR-autophagy pathway and the IRF3-IFN-β signaling network.","method":"Co-immunoprecipitation (CSFV C protein with OGDH), autophagy agonist/inhibitor treatment (rapamycin/3-MA), siRNA knockdown, overexpression experiments, NDP52/NBR1 interaction studies","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP establishing viral protein-OGDH interaction, pharmacological and genetic epistasis for pathway placement, single lab","pmids":["37604413"],"is_preprint":false},{"year":2024,"finding":"Loss of OGDH function (via CPI-613) causes energy deprivation that drives an integrated stress response with ATF4-dependent upregulation of the BH3-only protein Noxa; this is synthetically lethal with Bcl-xL inhibition (ABT263) in glioblastoma; silencing Noxa attenuates cell death, placing OGDH inhibition upstream of ATF4-Noxa in an apoptotic pathway.","method":"CPI-613 pharmacological inhibition, genetic loss-of-function (siRNA/CRISPR), transcriptome and metabolite screening, ATF4 and Noxa knockdown epistasis experiments, patient-derived xenograft models","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and pharmacological interventions with defined epistasis (ATF4→Noxa), validated in patient-derived xenograft models, multiple orthogonal methods","pmids":["38483541"],"is_preprint":false},{"year":2025,"finding":"RELA (NF-κB p65) transcriptionally regulates OGDH; ChIP-qPCR and luciferase reporter assays demonstrated that RELA binds the OGDH promoter; RELA knockdown reduces OGDH expression and impairs TCA cycle energy metabolism and cancer cell migration.","method":"ChIP-qPCR, luciferase reporter assay, gene editing, migration assays, metabolomics","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR and reporter assay establishing transcriptional regulation, single lab with two orthogonal methods","pmids":["39848017"],"is_preprint":false},{"year":2025,"finding":"ANGPT2 (upregulated by HCMV UL82) inhibits ubiquitin-mediated degradation of OGDH (deubiquitination), thereby maintaining OGDH protein stability; silencing ANGPT2 reduces OGDH protein levels, demonstrating post-translational regulation of OGDH via ubiquitination.","method":"Co-immunoprecipitation, siRNA knockdown of ANGPT2, ubiquitination pathway analysis, in vitro and in vivo proliferation assays","journal":"Tumour virus research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and genetic knockdown with protein stability readout, single lab with multiple methods","pmids":["40571161"],"is_preprint":false},{"year":2026,"finding":"OGDH physically interacts with catalase (CAT) and SOD2, and boosts their enzymatic activities; OGDH knockdown impairs AKG's ability to promote follicular development and antioxidative responses, placing OGDH as a mediator of AKG's protective effects through modulation of CAT/SOD2 antioxidant enzymes.","method":"Co-immunoprecipitation (OGDH with CAT and SOD2), enzymatic activity assays, OGDH knockdown, follicular development assays in mice","journal":"Biological research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP establishing physical interaction, enzymatic activity measurements, genetic loss-of-function with in vivo phenotype, single lab","pmids":["41964037"],"is_preprint":false},{"year":2025,"finding":"Under glutamine deficiency, OGDH shows increased nuclear localization in muscle progenitor cells, accompanied by elevated histone succinylation and restricted chromatin accessibility at the MyoD1 locus, linking OGDH nuclear translocation to epigenetic regulation of myogenesis.","method":"Confocal imaging of nuclear localization, succinyl-proteomics, single-cell nuclei ATAC sequencing, proliferation assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, confocal localization without direct functional mutagenesis of OGDH nuclear function, single lab","pmids":[],"is_preprint":true}],"current_model":"OGDH encodes the E1 (alpha-ketoglutarate dehydrogenase) subunit of the mitochondrial alpha-ketoglutarate dehydrogenase complex (OGDHC), which catalyzes the oxidative decarboxylation of alpha-ketoglutarate to succinyl-CoA in the TCA cycle; the complex can incorporate DHTKD1 to form a hybrid complex with expanded substrate specificity (including 2-oxoadipic acid); OGDH activity is regulated post-translationally by SIRT5-mediated desuccinylation (which inhibits OGDH), nitration under oxidative/diabetic conditions, and ubiquitin-mediated degradation (stabilized by ANGPT2); transcriptionally, OGDH is regulated by NF-κB/RELA and, in yeast, by HAP2/HAP3 in a catabolite-repressed manner; loss-of-function causes reduced TCA flux, impaired mitochondrial respiration, ATP depletion, elevated ROS, and accumulation of alpha-ketoglutarate, which regulates downstream autophagy and apoptosis (via ATF4-Noxa), and biallelic pathogenic variants in humans cause a neurodevelopmental disorder with metabolic abnormalities."},"narrative":{"mechanistic_narrative":"OGDH encodes the E1 (alpha-ketoglutarate dehydrogenase) subunit of the mitochondrial alpha-ketoglutarate dehydrogenase complex, which catalyzes oxidative decarboxylation in the TCA cycle and is essential for mitochondrial respiration, ATP production, redox balance, and cell viability [PMID:2503710, PMID:35500439]. Beyond the canonical complex, OGDH assembles with DHTKD1, DLST, and DLD into a hybrid 2-oxoglutarate/2-oxoadipate dehydrogenase complex, allowing it to consume 2-oxoadipic acid and contribute to glutaryl-CoA production when DHTKD1 is absent [PMID:32160276]. By consuming alpha-ketoglutarate, OGDH controls the intracellular level of this metabolite, which feeds back on autophagy and apoptosis: OGDH loss raises alpha-ketoglutarate and restores ATG-dependent autophagy downstream of p53 [PMID:30289354], while OGDH inhibition triggers an ATF4-dependent integrated stress response that upregulates the BH3-only protein Noxa, an axis synthetically lethal with Bcl-xL inhibition in glioblastoma [PMID:38483541]. OGDH activity is set post-translationally: SIRT5 directly binds and desuccinylates OGDH to inhibit complex activity [PMID:31247190], the protein is nitrated under diabetic/oxidative conditions [PMID:25251478], and its stability is governed by ubiquitin-mediated turnover that is opposed by ANGPT2 [PMID:40571161]. Transcriptionally, OGDH is a target of RELA (NF-κB p65), which binds its promoter and sustains TCA-driven energy metabolism and cancer cell migration [PMID:39848017]; in yeast the ortholog KGD1 is catabolite-repressed through HAP2/HAP3 [PMID:2503710]. OGDH dependency marks a metabolic vulnerability in cancers reliant on the malate-aspartate shuttle and supports proliferation, EMT/Wnt signaling, and tumor growth [PMID:27732861, PMID:31686854]. Biallelic loss-of-function variants in OGDH that reduce protein level and enzymatic activity cause a human neurodevelopmental disorder with metabolic abnormalities, established through patient-cell enzymology and cross-species Drosophila rescue [PMID:32383294, PMID:36520152].","teleology":[{"year":1989,"claim":"Established the identity of the gene as the E1 catalytic subunit of the alpha-ketoglutarate dehydrogenase complex and its transcriptional control, defining the core enzymatic function.","evidence":"Cloning by complementation, chromosomal disruption, and lacZ promoter reporter assays in yeast KGD1, with hap2/hap3 epistasis","pmids":["2503710"],"confidence":"High","gaps":["Yeast ortholog only; human regulatory architecture not addressed","Does not resolve subunit stoichiometry of the human complex"]},{"year":1994,"claim":"Localized the human OGDH gene, providing a genomic anchor for later disease-variant studies.","evidence":"Somatic cell hybrid panel mapping to chromosome 7p13-p11.2","pmids":["8020988"],"confidence":"Medium","gaps":["No functional or expression data","Relationship of the chromosome 10 related sequence to OGDH function unresolved"]},{"year":2016,"claim":"Showed OGDH is a selective metabolic dependency in cancer, answering whether a core TCA enzyme can be a context-specific vulnerability.","evidence":"siRNA screen, metabolomics, 3D proliferation and xenograft assays linking OGDH dependency to malate-aspartate shuttle reliance","pmids":["27732861"],"confidence":"High","gaps":["Biomarker basis of dependency beyond aspartate utilization incomplete","Does not address whether dependency generalizes outside the tested cancer types"]},{"year":2018,"claim":"Connected OGDH enzymatic flux to alpha-ketoglutarate-dependent control of autophagy and apoptosis downstream of p53.","evidence":"OGDH siRNA knockdown with cell-permeable alpha-ketoglutarate add-back and autophagy/ATG readouts in Nutlin-3a-treated cells","pmids":["30289354"],"confidence":"Medium","gaps":["Direct molecular target of alpha-ketoglutarate in autophagy regulation not identified","Single lab, single cell context"]},{"year":2019,"claim":"Identified SIRT5 desuccinylation as a direct post-translational switch inhibiting OGDH, and tied OGDH metabolic output to mitochondrial function and tumor signaling.","evidence":"Reciprocal Co-IP, succinyl phosphonate inhibition, siRNA epistasis, and metabolic/Wnt-EMT readouts in gastric cancer cells","pmids":["31247190","31686854"],"confidence":"High","gaps":["Specific succinylated lysine residues not mapped","Mechanistic link between OGDH metabolism and Wnt/β-catenin activation undefined"]},{"year":2020,"claim":"Defined a hybrid dehydrogenase complex and expanded OGDH substrate specificity, explaining its role in lysine/tryptophan degradation metabolism.","evidence":"Co-IP, mass spectrometry, and DHTKD1/GCDH KO HEK293 models with glutarylcarnitine quantification","pmids":["32160276"],"confidence":"High","gaps":["Stoichiometry and regulation of the hybrid complex unresolved","Physiological tissue contexts where the hybrid complex dominates not defined"]},{"year":2020,"claim":"Established OGDH loss-of-function variants as the cause of a human disease through enzymology and cross-species rescue.","evidence":"Whole exome sequencing, patient fibroblast enzymatic assays, HEK293 expression, and Drosophila rescue of lethality/locomotion","pmids":["32383294","36520152"],"confidence":"High","gaps":["Genotype-phenotype correlations across the variant spectrum incomplete","Tissue-specific basis of neurodevelopmental phenotype not resolved"]},{"year":2022,"claim":"Demonstrated that OGDH is essential for mitochondrial respiration and cell identity in human stem cells, generalizing its requirement beyond cancer.","evidence":"Inducible CRISPRi knockdown with metabolic flux, ATP, and RNA-seq analysis in primed hESCs","pmids":["35500439"],"confidence":"Medium","gaps":["Direct cause of transcriptional aberrations versus secondary metabolic stress not separated","Single lab"]},{"year":2023,"claim":"Revealed viral exploitation of OGDH, with CSFV targeting it for autophagic degradation and OGDH restraining infection via AMPK-mTOR and IRF3-IFN-β signaling.","evidence":"Co-IP of CSFV C protein with OGDH, NDP52/NBR1 interaction studies, autophagy modulators, and knockdown/overexpression","pmids":["37604413"],"confidence":"Medium","gaps":["Direct E3/receptor wiring of OGDH ubiquitination not fully defined","Mechanism linking OGDH levels to IRF3-IFN-β signaling unresolved"]},{"year":2024,"claim":"Placed OGDH inhibition upstream of an ATF4-Noxa apoptotic axis exploitable for synthetic lethality, advancing it as a therapeutic node.","evidence":"CPI-613 inhibition plus genetic loss-of-function with ATF4/Noxa epistasis and patient-derived xenograft validation in glioblastoma","pmids":["38483541"],"confidence":"High","gaps":["Specificity of CPI-613 for OGDH versus other dehydrogenases not fully isolated","Determinants of which tumors engage the ATF4-Noxa response undefined"]},{"year":2025,"claim":"Established additional layers of OGDH regulation: transcriptional activation by RELA and post-translational stabilization opposed by ANGPT2.","evidence":"ChIP-qPCR and luciferase reporter for RELA-promoter binding; Co-IP and ANGPT2 knockdown with ubiquitination/stability readouts","pmids":["39848017","40571161"],"confidence":"Medium","gaps":["Identity of the E3 ligase mediating OGDH ubiquitination not determined","Whether RELA regulation operates in non-cancer tissues unknown"]},{"year":2026,"claim":"Linked OGDH to antioxidant defense by physical interaction with and activation of catalase and SOD2, mediating protective effects of alpha-ketoglutarate.","evidence":"Co-IP of OGDH with CAT and SOD2, enzymatic activity assays, and knockdown with in vivo follicular development phenotypes in mice","pmids":["41964037"],"confidence":"Medium","gaps":["Mechanism by which OGDH boosts CAT/SOD2 activity unresolved","Single lab, reproductive-tissue context"]},{"year":null,"claim":"Whether OGDH has a bona fide nuclear, chromatin-modifying function distinct from its mitochondrial enzymatic role remains open.","evidence":"Preprint reporting glutamine-deficiency-induced nuclear OGDH, histone succinylation, and altered MyoD1 chromatin accessibility (bioRxiv)","pmids":[],"confidence":"Low","gaps":["Preprint; not peer-reviewed or independently confirmed","No direct mutagenesis isolating a nuclear OGDH function from mitochondrial loss","Mechanism of OGDH nuclear translocation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,7,8]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[11,6]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,7,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,13]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9,12]}],"complexes":["alpha-ketoglutarate dehydrogenase complex (OGDHC)","hybrid 2-oxoglutarate/2-oxoadipate dehydrogenase complex"],"partners":["DHTKD1","DLST","DLD","SIRT5","ANGPT2","CAT","SOD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q02218","full_name":"2-oxoglutarate dehydrogenase complex component E1","aliases":["2-oxoglutarate dehydrogenase, mitochondrial","Alpha-ketoglutarate dehydrogenase","Alpha-KGDH-E1","Thiamine diphosphate (ThDP)-dependent 2-oxoglutarate dehydrogenase"],"length_aa":1023,"mass_kda":115.9,"function":"2-oxoglutarate dehydrogenase (E1o) component of the 2-oxoglutarate dehydrogenase complex (OGDHC) (PubMed:24495017, PubMed:25210035, PubMed:28435050). Participates in the first step, rate limiting for the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2) catalyzed by the whole OGDHC (PubMed:24495017, PubMed:25210035, PubMed:28435050). Catalyzes the irreversible decarboxylation of 2-oxoglutarate (alpha-ketoglutarate) via the thiamine diphosphate (ThDP) cofactor and subsequent transfer of the decarboxylated acyl intermediate on an oxidized dihydrolipoyl group that is covalently amidated to the E2 enzyme (dihydrolipoyllysine-residue succinyltransferase or DLST) (PubMed:24495017, PubMed:25210035, PubMed:28435050, PubMed:35272141). Plays a key role in the Krebs (citric acid) cycle, which is a common pathway for oxidation of fuel molecules, including carbohydrates, fatty acids, and amino acids (PubMed:25210035). Can catalyze the decarboxylation of 2-oxoadipate in vitro, but at a much lower rate than 2-oxoglutarate (PubMed:28435050). Can also convert 2-keto-4-hydroxyglutarate (KHG) and CoA into malyl-CoA (By similarity). Mainly active in the mitochondrion (PubMed:29211711). A fraction of the 2-oxoglutarate dehydrogenase complex also localizes in the nucleus and is required for lysine succinylation of histones: associates with KAT2A on chromatin and provides succinyl-CoA to histone succinyltransferase KAT2A (PubMed:29211711)","subcellular_location":"Mitochondrion; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q02218/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OGDH","classification":"Not Classified","n_dependent_lines":576,"n_total_lines":1208,"dependency_fraction":0.4768211920529801},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OGDH","total_profiled":1310},"omim":[{"mim_id":"619701","title":"YOON-BELLEN NEURODEVELOPMENTAL SYNDROME; YOBELN","url":"https://www.omim.org/entry/619701"},{"mim_id":"618580","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 80; DEE80","url":"https://www.omim.org/entry/618580"},{"mim_id":"617513","title":"OXOGLUTARATE DEHYDROGENASE-LIKE PROTEIN; OGDHL","url":"https://www.omim.org/entry/617513"},{"mim_id":"616184","title":"CLUSTERED MITOCHONDRIA, D. DISCOIDEUM, HOMOLOG OF; CLUH","url":"https://www.omim.org/entry/616184"},{"mim_id":"614984","title":"DEHYDROGENASE E1 AND TRANSKETOLASE DOMAINS-CONTAINING PROTEIN 1; DHTKD1","url":"https://www.omim.org/entry/614984"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":302.2},{"tissue":"skeletal muscle","ntpm":340.6},{"tissue":"tongue","ntpm":349.9}],"url":"https://www.proteinatlas.org/search/OGDH"},"hgnc":{"alias_symbol":["E1k","OGDC-E1","OGDH2","KGD1"],"prev_symbol":[]},"alphafold":{"accession":"Q02218","domains":[{"cath_id":"-","chopping":"57-90","consensus_level":"medium","plddt":89.8244,"start":57,"end":90},{"cath_id":"-","chopping":"119-238","consensus_level":"high","plddt":88.4594,"start":119,"end":238},{"cath_id":"3.40.50.970","chopping":"252-583","consensus_level":"high","plddt":94.7994,"start":252,"end":583},{"cath_id":"3.40.50.12470","chopping":"610-781_831-873","consensus_level":"high","plddt":97.0053,"start":610,"end":873},{"cath_id":"3.40.50.11610","chopping":"885-1013","consensus_level":"high","plddt":96.5633,"start":885,"end":1013}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02218","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q02218-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q02218-F1-predicted_aligned_error_v6.png","plddt_mean":90.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OGDH","jax_strain_url":"https://www.jax.org/strain/search?query=OGDH"},"sequence":{"accession":"Q02218","fasta_url":"https://rest.uniprot.org/uniprotkb/Q02218.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q02218/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02218"}},"corpus_meta":[{"pmid":"2503710","id":"PMC_2503710","title":"Structure and regulation of KGD1, the structural gene for yeast alpha-ketoglutarate dehydrogenase.","date":"1989","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2503710","citation_count":100,"is_preprint":false},{"pmid":"30561685","id":"PMC_30561685","title":"Screening the ToxCast Phase 1, Phase 2, and e1k Chemical Libraries for Inhibitors of Iodothyronine Deiodinases.","date":"2019","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/30561685","citation_count":61,"is_preprint":false},{"pmid":"27732861","id":"PMC_27732861","title":"Differential Aspartate Usage Identifies a Subset of Cancer Cells Particularly Dependent on OGDH.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27732861","citation_count":60,"is_preprint":false},{"pmid":"31247190","id":"PMC_31247190","title":"OGDH mediates the inhibition of SIRT5 on cell proliferation and migration of gastric cancer.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31247190","citation_count":42,"is_preprint":false},{"pmid":"32383294","id":"PMC_32383294","title":"A biallelic pathogenic variant in the OGDH gene results in a neurological disorder with features of a mitochondrial disease.","date":"2020","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/32383294","citation_count":33,"is_preprint":false},{"pmid":"31686854","id":"PMC_31686854","title":"OGDH promotes the progression of gastric cancer by regulating mitochondrial bioenergetics and Wnt/β-catenin signal pathway.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31686854","citation_count":27,"is_preprint":false},{"pmid":"32160276","id":"PMC_32160276","title":"DHTKD1 and OGDH display substrate overlap in cultured cells and form a hybrid 2-oxo acid dehydrogenase complex in vivo.","date":"2020","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32160276","citation_count":26,"is_preprint":false},{"pmid":"4054903","id":"PMC_4054903","title":"Plasma cholinesterase variants. Family studies of the E1k gene.","date":"1985","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/4054903","citation_count":26,"is_preprint":false},{"pmid":"10385636","id":"PMC_10385636","title":"In situ nucleic acid detection of PDC-E2, BCOADC-E2, OGDC-E2, PDC-E1alpha, BCOADC-E1alpha, OGDC-E1, and the E3 binding protein (protein X) in primary biliary cirrhosis.","date":"1999","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/10385636","citation_count":22,"is_preprint":false},{"pmid":"33656581","id":"PMC_33656581","title":"Expanded high-throughput screening and chemotype-enrichment analysis of the phase II: e1k ToxCast library for human sodium-iodide symporter (NIS) inhibition.","date":"2021","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/33656581","citation_count":21,"is_preprint":false},{"pmid":"33854374","id":"PMC_33854374","title":"CircRNA circ-OGDH (hsa_circ_0003340) Acts as a ceRNA to Regulate Glutamine Metabolism and Esophageal Squamous Cell Carcinoma Progression by the miR-615-5p/PDX1 Axis.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33854374","citation_count":20,"is_preprint":false},{"pmid":"8014977","id":"PMC_8014977","title":"A PCR based method to determine the Kalow allele of the cholinesterase gene: the E1k allele frequency and its significance in the normal population.","date":"1994","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8014977","citation_count":19,"is_preprint":false},{"pmid":"25251478","id":"PMC_25251478","title":"A novel targeted proteomics method for identification and relative quantitation of difference in nitration degree of OGDH between healthy and diabetic mouse.","date":"2014","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/25251478","citation_count":19,"is_preprint":false},{"pmid":"8020988","id":"PMC_8020988","title":"Localization of the gene (OGDH) coding for the E1k component of the alpha-ketoglutarate dehydrogenase complex to chromosome 7p13-p11.2.","date":"1994","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8020988","citation_count":17,"is_preprint":false},{"pmid":"30289354","id":"PMC_30289354","title":"Alpha ketoglutarate levels, regulated by p53 and OGDH, determine autophagy and cell fate/apoptosis in response to Nutlin-3a.","date":"2018","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30289354","citation_count":14,"is_preprint":false},{"pmid":"34539976","id":"PMC_34539976","title":"Citrate Synthase and OGDH as Potential Biomarkers of Atherosclerosis under Chronic Stress.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/34539976","citation_count":14,"is_preprint":false},{"pmid":"27468871","id":"PMC_27468871","title":"Frameshift mutations of OGDH, PPAT and PCCA genes in gastric and colorectal cancers.","date":"2016","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/27468871","citation_count":13,"is_preprint":false},{"pmid":"37604413","id":"PMC_37604413","title":"Role of OGDH in Atophagy-IRF3-IFN-β pathway during classical swine fever virus infection.","date":"2023","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37604413","citation_count":12,"is_preprint":false},{"pmid":"38483541","id":"PMC_38483541","title":"OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.","date":"2024","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/38483541","citation_count":10,"is_preprint":false},{"pmid":"36520152","id":"PMC_36520152","title":"Biallelic variants in OGDH encoding oxoglutarate dehydrogenase lead to a neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities.","date":"2022","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36520152","citation_count":10,"is_preprint":false},{"pmid":"3019402","id":"PMC_3019402","title":"Nucleotide specificity of the E2K----E1K transition in (Na+ + K+)-ATPase as probed with tryptic inactivation and fragmentation.","date":"1986","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/3019402","citation_count":10,"is_preprint":false},{"pmid":"16901643","id":"PMC_16901643","title":"Identification and mRNA expression of Ogdh, QP-C, and two predicted genes in the postnatal mouse brain.","date":"2006","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/16901643","citation_count":8,"is_preprint":false},{"pmid":"39848017","id":"PMC_39848017","title":"Modified Shenqi Dihuang Decoction inhibits prostate cancer metastasis by disrupting TCA cycle energy metabolism via NF-kB/p65-mediated OGDH regulation.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39848017","citation_count":7,"is_preprint":false},{"pmid":"15459651","id":"PMC_15459651","title":"PCR method based on the ogdH gene for the detection of Salmonella spp. from chicken meat samples.","date":"2004","source":"Journal of microbiology (Seoul, Korea)","url":"https://pubmed.ncbi.nlm.nih.gov/15459651","citation_count":7,"is_preprint":false},{"pmid":"40412523","id":"PMC_40412523","title":"Circular RNA-OGDH promotes PANoptosis in diabetic cardiomyopathy: A novel mechanistic insight.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40412523","citation_count":6,"is_preprint":false},{"pmid":"35500439","id":"PMC_35500439","title":"The functional role of OGDH for maintaining mitochondrial respiration and identity of primed human embryonic stem cells.","date":"2022","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/35500439","citation_count":6,"is_preprint":false},{"pmid":"34527342","id":"PMC_34527342","title":"OGDH is involved in sepsis induced acute lung injury through the MAPK pathway.","date":"2021","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/34527342","citation_count":6,"is_preprint":false},{"pmid":"8299151","id":"PMC_8299151","title":"The ogd1 and kgd1 mutants lacking 2-oxoglutarate dehydrogenase activity in yeast are allelic and can be differentiated by the cloned amber suppressor.","date":"1993","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8299151","citation_count":3,"is_preprint":false},{"pmid":"40571161","id":"PMC_40571161","title":"Human cytomegalovirus UL82 promotes colorectal cancer cell proliferation through inhibiting the ubiquitination of OGDH via ANGPT2.","date":"2025","source":"Tumour virus research","url":"https://pubmed.ncbi.nlm.nih.gov/40571161","citation_count":0,"is_preprint":false},{"pmid":"41317892","id":"PMC_41317892","title":"E1K, a disease-modifying drug candidate for knee osteoarthritis, alleviates pain and regenerates cartilage simultaneously by inhibiting TGF-β1-mediated SMAD1/5/9 signaling in osteoarthritis models.","date":"2025","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/41317892","citation_count":0,"is_preprint":false},{"pmid":"40887492","id":"PMC_40887492","title":"ACO1 OGDH axis drives mitochondrial immune crosstalk in preeclampsia through systems biology enabling dual target therapy.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40887492","citation_count":0,"is_preprint":false},{"pmid":"42079189","id":"PMC_42079189","title":"Simultaneous Inhibition of ACLY and OGDH Has a Synergistic Effect on Hepatocellular Carcinoma Cell Lines.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42079189","citation_count":0,"is_preprint":false},{"pmid":"42143323","id":"PMC_42143323","title":"OGDH primes macrophage for M1-like polarization and ferroptosis in sepsis associated acute lung injury.","date":"2026","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/42143323","citation_count":0,"is_preprint":false},{"pmid":"41964037","id":"PMC_41964037","title":"OGDH mediates α-ketoglutarate-induced follicular development and antioxidative response by interacting with CAT/SOD2.","date":"2026","source":"Biological research","url":"https://pubmed.ncbi.nlm.nih.gov/41964037","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.17.676232","title":"Integrative Analysis of Left Ventricle and Epicardial Adipose Tissue Identifies SDHA and OGDH as Candidate Targets for Ischemic Heart Disease","date":"2025-09-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.17.676232","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.15.669572","title":"Hypobaric hypoxia drives citrate cycle reprogramming to suppress tumor progression","date":"2025-08-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.15.669572","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.24.671070","title":"Cross-species analysis identifies genotype-driven vulnerabilities in lung adenocarcinoma","date":"2025-08-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.24.671070","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.30.657066","title":"Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing myogenesis","date":"2025-06-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.30.657066","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.28.656673","title":"OGDHL regulates tumor growth, neuroendocrine marker expression, and nucleotide abundance in prostate cancer","date":"2025-06-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.28.656673","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22774,"output_tokens":4683,"usd":0.069283,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12852,"output_tokens":4138,"usd":0.083855,"stage2_stop_reason":"end_turn"},"total_usd":0.153138,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"KGD1 (yeast ortholog of OGDH) encodes the alpha-ketoglutarate dehydrogenase (E1) component of the alpha-ketoglutarate dehydrogenase complex; disruption of the chromosomal copy causes deficiency in alpha-ketoglutarate dehydrogenase activity, and the gene is catabolite repressed via HAP2/HAP3 regulatory proteins binding to a promoter element between -354 and -143.\",\n      \"method\": \"Gene cloning by complementation of kgd1 mutants, chromosomal disruption (kgd1::URA3), lacZ fusion reporter assays, testing in hap2/hap3 mutant backgrounds\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic disruption with defined enzymatic phenotype, promoter mapping with reporter assays, and regulatory epistasis via hap2/hap3 mutants in a single rigorous study\",\n      \"pmids\": [\"2503710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The ogd1 and kgd1 mutations in yeast, both abolishing 2-oxoglutarate dehydrogenase activity, are allelic (same gene locus), as demonstrated by complementation and meiotic mapping.\",\n      \"method\": \"Complementation assay, allelism test, meiotic mapping\",\n      \"journal\": \"Current genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic complementation and meiotic mapping from a single study with two orthogonal methods\",\n      \"pmids\": [\"8299151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The OGDH gene (encoding E1k, the E1 subunit of alpha-ketoglutarate dehydrogenase complex) was mapped to human chromosome 7p13-p11.2; a second related sequence (possibly a pseudogene) was mapped to chromosome 10.\",\n      \"method\": \"Somatic cell hybrid panel mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal localization using somatic cell hybrids, single lab\",\n      \"pmids\": [\"8020988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OGDH protein undergoes tyrosine/tryptophan nitration in myocardial tissue, and the degree of nitration is higher in diabetic mice compared to controls, indicating that OGDH is subject to oxidative post-translational modification (nitration) that is elevated under diabetic conditions.\",\n      \"method\": \"Targeted proteomics using parallel reaction monitoring (PRM) and selected reaction monitoring (SRM) mass spectrometry via Skyline-designed methods\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — targeted MS-based identification of nitration sites with relative quantitation, single lab, single method\",\n      \"pmids\": [\"25251478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"OGDH (E1 subunit of the alpha-ketoglutarate dehydrogenase complex) is required for cancer cell proliferation in 3D culture and xenograft tumor growth in a subset of cancer cells that rely on the malate-aspartate shuttle; differential aspartate utilization predicts OGDH dependency.\",\n      \"method\": \"siRNA screen of TCA cycle enzymes, integrative metabolomics, 3D proliferation assays, xenograft tumor growth assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown with defined metabolic and proliferative phenotypes, multiple orthogonal methods (metabolomics + 3D + xenograft), single lab\",\n      \"pmids\": [\"27732861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT5 directly interacts with OGDH and desuccinylates OGDH, which inhibits OGDH complex activity; OGDH inhibition (by succinyl phosphonate or siRNA) suppresses cell growth and migration induced by SIRT5 deletion, placing OGDH downstream of SIRT5 in gastric cancer cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, succinyl phosphonate inhibitor treatment, cell growth/migration assays, measurement of mitochondrial membrane potential, ATP, ROS, and NADP+/NADPH ratio\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP establishing direct interaction, genetic/pharmacological epistasis placing OGDH downstream of SIRT5, multiple metabolic readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31247190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OGDH knockdown in gastric cancer cells decreases mitochondrial membrane potential, oxygen consumption rate, ATP production, and increases ROS and NADP+/NADPH ratio; OGDH overexpression has opposite effects; furthermore, OGDH knockdown reduces Wnt/β-catenin pathway components (β-catenin, slug, TCF8/ZEB1, cyclin D1, MMP9) while overexpression activates this pathway.\",\n      \"method\": \"siRNA knockdown, overexpression, OCR measurement, ATP assay, ROS measurement, Western blotting for EMT and Wnt pathway markers, xenograft tumor model\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — loss- and gain-of-function with multiple metabolic and signaling readouts, single lab\",\n      \"pmids\": [\"31686854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OGDH interacts with DHTKD1, dihydrolipoyl succinyltransferase (DLST), and dihydrolipoamide dehydrogenase (DLD) to form a hybrid 2-oxoglutaric and 2-oxoadipic acid dehydrogenase complex; OGDH can use 2-oxoadipic acid as a substrate (in addition to 2-oxoglutarate), contributing to glutaryl-CoA production in cells lacking DHTKD1.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, HEK-293 cell genetic models (DHTKD1 KO + GCDH KO), metabolite quantification (glutarylcarnitine)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP establishing complex composition, genetic cell models with metabolite readouts, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"32160276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Biallelic loss-of-function variants in OGDH (p.N320S) reduce OGDH protein levels and enzymatic activity in patient fibroblasts and HEK293 cells; expression of mutant OGDH fails to rescue developmental lethality and locomotion defects caused by loss of Drosophila Ogdh, establishing that these variants cause severe loss of OGDH protein function.\",\n      \"method\": \"Whole exome sequencing, patient fibroblast enzymatic assay, HEK293 transfection with WT vs mutant cDNA, Drosophila rescue experiments (lethality and locomotion assays)\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — enzymatic activity measurements in patient cells, protein quantification, and cross-species functional rescue experiments with multiple orthogonal methods\",\n      \"pmids\": [\"32383294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"OGDH activity regulates intracellular alpha-ketoglutarate (αKG) levels; OGDH knockdown increases endogenous αKG levels and rescues cells from p53 activator Nutlin-3a-induced apoptosis by restoring autophagy and ATG gene expression, placing OGDH downstream of p53 in the regulation of αKG-dependent autophagy and apoptosis.\",\n      \"method\": \"OGDH siRNA knockdown, cell-permeable αKG analog (DMKG) add-back, autophagy assays, ATG gene expression analysis in Nutlin-3a-treated cells\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — loss-of-function with metabolite add-back rescue, multiple pathway readouts, single lab\",\n      \"pmids\": [\"30289354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Novel homozygous missense variants in OGDH (p.Pro189Leu and p.Ser297Tyr) cause accelerated protein degradation and reduced protein levels; expression in HEK293 cells shows lower protein levels than WT, and neither variant rescues developmental lethality of Drosophila Ogdh null mutants, confirming these are loss-of-function variants.\",\n      \"method\": \"Exome sequencing, in silico homology modeling, protein stability assays in patient fibroblasts and HEK293 cells, Drosophila rescue experiments, mini-gene splicing assay for a splice-site variant\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (protein quantification, splice assay, Drosophila rescue) across independent patient-derived and cell-line models\",\n      \"pmids\": [\"36520152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OGDH knockdown in human embryonic stem cells (hESCs) via inducible CRISPRi disrupts the TCA cycle, diminishes mitochondrial respiration activity, reduces total ATP levels, and leads to cell death and aberrant transcriptional programs, establishing OGDH as essential for mitochondrial respiration and identity maintenance in primed hESCs.\",\n      \"method\": \"CRISPRi-mediated knockdown, metabolic flux analysis, ATP measurement, RNA-seq transcriptomics, pharmacological ETC inhibition for comparison\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible genetic loss-of-function with multiple metabolic readouts and transcriptomic profiling, single lab\",\n      \"pmids\": [\"35500439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CSFV C protein interacts with OGDH protein; CSFV uses autophagy receptors NDP52/NBR1 to target OGDH for degradation via the autophagy-lysosome pathway, reducing OGDH levels and promoting α-KG secretion; OGDH overexpression inhibits CSFV proliferation through modulation of the AMPK-mTOR-autophagy pathway and the IRF3-IFN-β signaling network.\",\n      \"method\": \"Co-immunoprecipitation (CSFV C protein with OGDH), autophagy agonist/inhibitor treatment (rapamycin/3-MA), siRNA knockdown, overexpression experiments, NDP52/NBR1 interaction studies\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP establishing viral protein-OGDH interaction, pharmacological and genetic epistasis for pathway placement, single lab\",\n      \"pmids\": [\"37604413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of OGDH function (via CPI-613) causes energy deprivation that drives an integrated stress response with ATF4-dependent upregulation of the BH3-only protein Noxa; this is synthetically lethal with Bcl-xL inhibition (ABT263) in glioblastoma; silencing Noxa attenuates cell death, placing OGDH inhibition upstream of ATF4-Noxa in an apoptotic pathway.\",\n      \"method\": \"CPI-613 pharmacological inhibition, genetic loss-of-function (siRNA/CRISPR), transcriptome and metabolite screening, ATF4 and Noxa knockdown epistasis experiments, patient-derived xenograft models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and pharmacological interventions with defined epistasis (ATF4→Noxa), validated in patient-derived xenograft models, multiple orthogonal methods\",\n      \"pmids\": [\"38483541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RELA (NF-κB p65) transcriptionally regulates OGDH; ChIP-qPCR and luciferase reporter assays demonstrated that RELA binds the OGDH promoter; RELA knockdown reduces OGDH expression and impairs TCA cycle energy metabolism and cancer cell migration.\",\n      \"method\": \"ChIP-qPCR, luciferase reporter assay, gene editing, migration assays, metabolomics\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR and reporter assay establishing transcriptional regulation, single lab with two orthogonal methods\",\n      \"pmids\": [\"39848017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANGPT2 (upregulated by HCMV UL82) inhibits ubiquitin-mediated degradation of OGDH (deubiquitination), thereby maintaining OGDH protein stability; silencing ANGPT2 reduces OGDH protein levels, demonstrating post-translational regulation of OGDH via ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of ANGPT2, ubiquitination pathway analysis, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Tumour virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and genetic knockdown with protein stability readout, single lab with multiple methods\",\n      \"pmids\": [\"40571161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"OGDH physically interacts with catalase (CAT) and SOD2, and boosts their enzymatic activities; OGDH knockdown impairs AKG's ability to promote follicular development and antioxidative responses, placing OGDH as a mediator of AKG's protective effects through modulation of CAT/SOD2 antioxidant enzymes.\",\n      \"method\": \"Co-immunoprecipitation (OGDH with CAT and SOD2), enzymatic activity assays, OGDH knockdown, follicular development assays in mice\",\n      \"journal\": \"Biological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP establishing physical interaction, enzymatic activity measurements, genetic loss-of-function with in vivo phenotype, single lab\",\n      \"pmids\": [\"41964037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under glutamine deficiency, OGDH shows increased nuclear localization in muscle progenitor cells, accompanied by elevated histone succinylation and restricted chromatin accessibility at the MyoD1 locus, linking OGDH nuclear translocation to epigenetic regulation of myogenesis.\",\n      \"method\": \"Confocal imaging of nuclear localization, succinyl-proteomics, single-cell nuclei ATAC sequencing, proliferation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, confocal localization without direct functional mutagenesis of OGDH nuclear function, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"OGDH encodes the E1 (alpha-ketoglutarate dehydrogenase) subunit of the mitochondrial alpha-ketoglutarate dehydrogenase complex (OGDHC), which catalyzes the oxidative decarboxylation of alpha-ketoglutarate to succinyl-CoA in the TCA cycle; the complex can incorporate DHTKD1 to form a hybrid complex with expanded substrate specificity (including 2-oxoadipic acid); OGDH activity is regulated post-translationally by SIRT5-mediated desuccinylation (which inhibits OGDH), nitration under oxidative/diabetic conditions, and ubiquitin-mediated degradation (stabilized by ANGPT2); transcriptionally, OGDH is regulated by NF-κB/RELA and, in yeast, by HAP2/HAP3 in a catabolite-repressed manner; loss-of-function causes reduced TCA flux, impaired mitochondrial respiration, ATP depletion, elevated ROS, and accumulation of alpha-ketoglutarate, which regulates downstream autophagy and apoptosis (via ATF4-Noxa), and biallelic pathogenic variants in humans cause a neurodevelopmental disorder with metabolic abnormalities.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OGDH encodes the E1 (alpha-ketoglutarate dehydrogenase) subunit of the mitochondrial alpha-ketoglutarate dehydrogenase complex, which catalyzes oxidative decarboxylation in the TCA cycle and is essential for mitochondrial respiration, ATP production, redox balance, and cell viability [#0, #11]. Beyond the canonical complex, OGDH assembles with DHTKD1, DLST, and DLD into a hybrid 2-oxoglutarate/2-oxoadipate dehydrogenase complex, allowing it to consume 2-oxoadipic acid and contribute to glutaryl-CoA production when DHTKD1 is absent [#7]. By consuming alpha-ketoglutarate, OGDH controls the intracellular level of this metabolite, which feeds back on autophagy and apoptosis: OGDH loss raises alpha-ketoglutarate and restores ATG-dependent autophagy downstream of p53 [#9], while OGDH inhibition triggers an ATF4-dependent integrated stress response that upregulates the BH3-only protein Noxa, an axis synthetically lethal with Bcl-xL inhibition in glioblastoma [#13]. OGDH activity is set post-translationally: SIRT5 directly binds and desuccinylates OGDH to inhibit complex activity [#5], the protein is nitrated under diabetic/oxidative conditions [#3], and its stability is governed by ubiquitin-mediated turnover that is opposed by ANGPT2 [#15]. Transcriptionally, OGDH is a target of RELA (NF-\\u03baB p65), which binds its promoter and sustains TCA-driven energy metabolism and cancer cell migration [#14]; in yeast the ortholog KGD1 is catabolite-repressed through HAP2/HAP3 [#0]. OGDH dependency marks a metabolic vulnerability in cancers reliant on the malate-aspartate shuttle and supports proliferation, EMT/Wnt signaling, and tumor growth [#4, #6]. Biallelic loss-of-function variants in OGDH that reduce protein level and enzymatic activity cause a human neurodevelopmental disorder with metabolic abnormalities, established through patient-cell enzymology and cross-species Drosophila rescue [#8, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Established the identity of the gene as the E1 catalytic subunit of the alpha-ketoglutarate dehydrogenase complex and its transcriptional control, defining the core enzymatic function.\",\n      \"evidence\": \"Cloning by complementation, chromosomal disruption, and lacZ promoter reporter assays in yeast KGD1, with hap2/hap3 epistasis\",\n      \"pmids\": [\"2503710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast ortholog only; human regulatory architecture not addressed\", \"Does not resolve subunit stoichiometry of the human complex\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Localized the human OGDH gene, providing a genomic anchor for later disease-variant studies.\",\n      \"evidence\": \"Somatic cell hybrid panel mapping to chromosome 7p13-p11.2\",\n      \"pmids\": [\"8020988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or expression data\", \"Relationship of the chromosome 10 related sequence to OGDH function unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed OGDH is a selective metabolic dependency in cancer, answering whether a core TCA enzyme can be a context-specific vulnerability.\",\n      \"evidence\": \"siRNA screen, metabolomics, 3D proliferation and xenograft assays linking OGDH dependency to malate-aspartate shuttle reliance\",\n      \"pmids\": [\"27732861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biomarker basis of dependency beyond aspartate utilization incomplete\", \"Does not address whether dependency generalizes outside the tested cancer types\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected OGDH enzymatic flux to alpha-ketoglutarate-dependent control of autophagy and apoptosis downstream of p53.\",\n      \"evidence\": \"OGDH siRNA knockdown with cell-permeable alpha-ketoglutarate add-back and autophagy/ATG readouts in Nutlin-3a-treated cells\",\n      \"pmids\": [\"30289354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of alpha-ketoglutarate in autophagy regulation not identified\", \"Single lab, single cell context\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified SIRT5 desuccinylation as a direct post-translational switch inhibiting OGDH, and tied OGDH metabolic output to mitochondrial function and tumor signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, succinyl phosphonate inhibition, siRNA epistasis, and metabolic/Wnt-EMT readouts in gastric cancer cells\",\n      \"pmids\": [\"31247190\", \"31686854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific succinylated lysine residues not mapped\", \"Mechanistic link between OGDH metabolism and Wnt/\\u03b2-catenin activation undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a hybrid dehydrogenase complex and expanded OGDH substrate specificity, explaining its role in lysine/tryptophan degradation metabolism.\",\n      \"evidence\": \"Co-IP, mass spectrometry, and DHTKD1/GCDH KO HEK293 models with glutarylcarnitine quantification\",\n      \"pmids\": [\"32160276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and regulation of the hybrid complex unresolved\", \"Physiological tissue contexts where the hybrid complex dominates not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established OGDH loss-of-function variants as the cause of a human disease through enzymology and cross-species rescue.\",\n      \"evidence\": \"Whole exome sequencing, patient fibroblast enzymatic assays, HEK293 expression, and Drosophila rescue of lethality/locomotion\",\n      \"pmids\": [\"32383294\", \"36520152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype correlations across the variant spectrum incomplete\", \"Tissue-specific basis of neurodevelopmental phenotype not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that OGDH is essential for mitochondrial respiration and cell identity in human stem cells, generalizing its requirement beyond cancer.\",\n      \"evidence\": \"Inducible CRISPRi knockdown with metabolic flux, ATP, and RNA-seq analysis in primed hESCs\",\n      \"pmids\": [\"35500439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cause of transcriptional aberrations versus secondary metabolic stress not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed viral exploitation of OGDH, with CSFV targeting it for autophagic degradation and OGDH restraining infection via AMPK-mTOR and IRF3-IFN-\\u03b2 signaling.\",\n      \"evidence\": \"Co-IP of CSFV C protein with OGDH, NDP52/NBR1 interaction studies, autophagy modulators, and knockdown/overexpression\",\n      \"pmids\": [\"37604413\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct E3/receptor wiring of OGDH ubiquitination not fully defined\", \"Mechanism linking OGDH levels to IRF3-IFN-\\u03b2 signaling unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed OGDH inhibition upstream of an ATF4-Noxa apoptotic axis exploitable for synthetic lethality, advancing it as a therapeutic node.\",\n      \"evidence\": \"CPI-613 inhibition plus genetic loss-of-function with ATF4/Noxa epistasis and patient-derived xenograft validation in glioblastoma\",\n      \"pmids\": [\"38483541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specificity of CPI-613 for OGDH versus other dehydrogenases not fully isolated\", \"Determinants of which tumors engage the ATF4-Noxa response undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established additional layers of OGDH regulation: transcriptional activation by RELA and post-translational stabilization opposed by ANGPT2.\",\n      \"evidence\": \"ChIP-qPCR and luciferase reporter for RELA-promoter binding; Co-IP and ANGPT2 knockdown with ubiquitination/stability readouts\",\n      \"pmids\": [\"39848017\", \"40571161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the E3 ligase mediating OGDH ubiquitination not determined\", \"Whether RELA regulation operates in non-cancer tissues unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked OGDH to antioxidant defense by physical interaction with and activation of catalase and SOD2, mediating protective effects of alpha-ketoglutarate.\",\n      \"evidence\": \"Co-IP of OGDH with CAT and SOD2, enzymatic activity assays, and knockdown with in vivo follicular development phenotypes in mice\",\n      \"pmids\": [\"41964037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which OGDH boosts CAT/SOD2 activity unresolved\", \"Single lab, reproductive-tissue context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether OGDH has a bona fide nuclear, chromatin-modifying function distinct from its mitochondrial enzymatic role remains open.\",\n      \"evidence\": \"Preprint reporting glutamine-deficiency-induced nuclear OGDH, histone succinylation, and altered MyoD1 chromatin accessibility (bioRxiv)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint; not peer-reviewed or independently confirmed\", \"No direct mutagenesis isolating a nuclear OGDH function from mitochondrial loss\", \"Mechanism of OGDH nuclear translocation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 7, 8]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [11, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 7, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9, 12]}\n    ],\n    \"complexes\": [\"alpha-ketoglutarate dehydrogenase complex (OGDHC)\", \"hybrid 2-oxoglutarate/2-oxoadipate dehydrogenase complex\"],\n    \"partners\": [\"DHTKD1\", \"DLST\", \"DLD\", \"SIRT5\", \"ANGPT2\", \"CAT\", \"SOD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}