{"gene":"OGDHL","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2012,"finding":"Forced OGDHL expression in cervical cancer cells increased ROS production, leading to apoptosis through caspase-3-mediated downregulation of AKT signaling and decreased NF-κB phosphorylation; conversely, OGDHL knockdown increased AKT phosphorylation. Addition of caspase-3 or ROS inhibitors in the presence of OGDHL rescued AKT signaling and cell proliferation, placing OGDHL upstream of ROS→caspase-3→AKT/NF-κB.","method":"Overexpression and shRNA knockdown in cervical cancer cells; ROS measurement; caspase-3 activity; phospho-AKT and phospho-NF-κB immunoblotting; caspase/ROS inhibitor rescue experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal functional methods (OE + KD) with rescue experiments; single lab, no in vitro reconstitution","pmids":["23152800"],"is_preprint":false},{"year":2019,"finding":"OGDHL downregulation reduced OGDH complex (OGDHC) activity, raising the α-ketoglutarate:citrate ratio and driving reductive carboxylation of glutamine-derived αKG via retrograde TCA cycling in hepatoma cells. Elevated αKG activated mTORC1 signaling, inducing transcription of de novo lipogenesis enzymes and providing NADPH/glutathione for antioxidant defense.","method":"OGDHL overexpression and knockdown in hepatoma cells and mouse xenografts; OGDHC activity assay; metabolite profiling (αKG:citrate ratio); isotope tracing of reductive glutamine carboxylation; mTORC1 pathway immunoblotting; lipogenesis enzyme expression analysis","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (enzymatic activity, metabolic tracing, in vivo xenograft, pathway immunoblotting) in one study with functional rescue","pmids":["31899205"],"is_preprint":false},{"year":2018,"finding":"shRNA-mediated disruption of OGDHL expression in esophageal epithelial cells blunted mitochondrial function (measured by oxygen consumption/respiration assays), establishing OGDHL as required for normal mitochondrial respiratory activity.","method":"shRNA knockdown in esophageal epithelial cells and patient fibroblasts; mitochondrial function assays (respirometry)","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function with mitochondrial functional readout; single lab, limited mechanistic depth in abstract","pmids":["29669943"],"is_preprint":false},{"year":2021,"finding":"Pan-neuronal knockout of dOgdh (Drosophila ortholog of OGDHL) caused developmental lethality and defects in Krebs cycle metabolism rescued by wild-type dOgdh cDNA. Patient missense variants (p.Arg673Gln, p.Phe734Ser, p.Arg299Gly) behaved as severe loss-of-function alleles causing lethality, while others (p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, p.Arg244Trp) were hypomorphic. Human neuronal cells with OGDHL knockout showed defects in mitochondrial respiration.","method":"CRISPR-Cas9 tissue-specific knockout of dOgdh in Drosophila with cDNA rescue; Krebs cycle metabolite measurement; behavioral assays; OGDHL KO human neuronal cells with mitochondrial respirometry; splicing analysis of synonymous variant p.Val488Val in patient fibroblasts","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution/rescue in Drosophila, mutagenesis across multiple alleles, human neuronal KO with respirometry, replicated across multiple families","pmids":["34800363"],"is_preprint":false},{"year":2023,"finding":"FTO-mediated m6A demethylation suppressed OGDHL expression in clear cell renal cell carcinoma (ccRCC). Low OGDHL levels promoted TFAP2A expression by inhibiting its ubiquitination; TFAP2A then bound the FASN promoter to transcriptionally activate FASN, promoting lipid accumulation and ERK pathway activation.","method":"RNA methylation immunoprecipitation (MeRIP); luciferase reporter assays; chromatin immunoprecipitation (ChIP); mutagenesis; FTO overexpression/knockdown; ubiquitination assays; OGDHL OE/KD in vitro and in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MeRIP, ChIP, luciferase, mutagenesis, ubiquitination assay) in a single lab study","pmids":["37626053"],"is_preprint":false},{"year":2023,"finding":"OGDHL silencing in HCC cells promoted accumulation of L-2-hydroxyglutarate (L-2-HG), which inhibited HIF-1α prolyl hydroxylases, stabilizing HIF-1α protein and enhancing its transactivation activity, thereby inducing epithelial-mesenchymal transition (EMT) and promoting metastasis.","method":"OGDHL overexpression and knockdown in HCC cells; in vivo metastasis models; L-2-HG metabolite measurement; HIF-1α protein stability assays; prolyl hydroxylase activity; EMT marker expression","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway established by metabolite measurement plus functional in vitro/in vivo assays; single lab","pmids":["36000493"],"is_preprint":false},{"year":2021,"finding":"OGDHL overexpression in 3×Tg-AD mice reduced neuroinflammation, amyloid plaque load, and tau phosphorylation, and activated Wnt/β-catenin signaling (evidenced by increased Wnt7B expression) in vitro, linking OGDHL to neuroprotection via this pathway.","method":"OGDHL overexpression in 3×Tg-AD mice (Western blot, immunohistochemistry, qPCR); behavioral memory assays; Wnt7B expression in vitro","journal":"Behavioural brain research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vivo overexpression with pathway marker readout but limited mechanistic depth in the abstract; single lab, single method per pathway","pmids":["34798170"],"is_preprint":false},{"year":2022,"finding":"A non-synonymous OGDHL variant rs2293239 (p.Asn725Ser) was predicted by computational modeling to cause a conformational change in the transketolase domain that reduces binding affinity for the cofactor thiamine pyrophosphate, resulting in abnormal glutamate accumulation in the brain.","method":"Whole-exome sequencing; structural/computational conformational analysis; brain imaging of variant carriers","journal":"Frontiers in psychiatry","confidence":"Low","confidence_rationale":"Tier 4 / Weak — mechanism inferred from computational modeling with no in vitro biochemical validation of TPP binding","pmids":["35370858"],"is_preprint":false},{"year":2023,"finding":"OGDHL and OGDH paralogs (OGDH, DHTKD1) exhibit complex transcriptional compensation and partial functional redundancy in zebrafish; ogdhl knockout zebrafish were rescued by human cDNA carrying various patient variants, with some alleles showing loss-of-function and others hypomorphic effects, indicating allele-specific functional differences at the enzyme level.","method":"CRISPR/Cas9 zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1; functional complementation with patient variant human cDNA transcripts; developmental phenotyping","journal":"Genome medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo CRISPR KO with cDNA rescue and multiple alleles tested; single lab but rigorous complementation design","pmids":["38031187"],"is_preprint":false},{"year":2025,"finding":"Co-immunoprecipitation confirmed that OGDHL physically interacts with PDHB (pyruvate dehydrogenase E1-β subunit) in gastric cancer cells. Downregulation of OGDHL destabilized PDHB protein, reducing pyruvate oxidative decarboxylation and decreasing acetyl-CoA and ATP production.","method":"Co-immunoprecipitation (Co-IP); si-OGDHL knockdown; PDHB protein stability assessment; acetyl-CoA and ATP measurement; in vivo tumor-bearing mouse models","journal":"Discover oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing physical interaction plus functional metabolic readouts; single lab","pmids":["41420718"],"is_preprint":false},{"year":2025,"finding":"In prostate cancer cells, OGDHL loss impaired proliferation and reduced nucleotide synthesis, induced γH2AX (DNA damage marker) accumulation, and suppressed androgen receptor inhibition-induced neuroendocrine marker expression (DLL3, HES6). Crucially, mitochondrial localization of OGDHL was found to be dispensable for its regulation of nucleotide metabolism and lineage plasticity, suggesting an extra-mitochondrial function.","method":"OGDHL knockdown in prostate cancer cell lines and xenografts; nucleotide abundance measurement; γH2AX immunoblotting; neuroendocrine marker expression; mitochondrial localization mutant constructs","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal readouts including localization mutant; single lab","pmids":["41591383"],"is_preprint":false},{"year":2025,"finding":"DICAR-JP (a peptide sequence) interacted with NACα (nascent polypeptide-associated complex alpha) to regulate OGDHL nascent peptide expression and facilitate translocation of OGDHL from cytoplasmic ribosomes to mitochondria, as measured by in vitro translation and SPR binding assays.","method":"Surface plasmon resonance (SPR) for DICAR-JP/NACα binding; in vitro translation assay; biotin-DICAR-JP pulldown; untargeted metabolomics; AAV9-mediated overexpression in db/db mice","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, novel mechanistic claim (ribosome migration) not yet peer-reviewed; SPR and in vitro translation support interaction but full validation absent","pmids":["40502162"],"is_preprint":true}],"current_model":"OGDHL is a brain-enriched, rate-limiting component of the α-ketoglutarate dehydrogenase complex (OGDHC) that catalyzes a key step in the TCA cycle; its loss reduces OGDHC activity, elevates the αKG:citrate ratio, drives reductive glutamine carboxylation, activates mTORC1-dependent lipogenesis, stabilizes HIF-1α via L-2-HG accumulation, and suppresses AKT/NF-κB signaling through ROS–caspase-3, while bi-allelic loss-of-function variants cause a Mendelian neurodevelopmental disorder characterized by epilepsy, hearing loss, and mitochondrial respiratory defects; in prostate cancer, OGDHL paradoxically supports nucleotide synthesis and neuroendocrine lineage plasticity independently of mitochondrial localization, and it physically interacts with PDHB to regulate pyruvate metabolism."},"narrative":{"mechanistic_narrative":"OGDHL is a rate-limiting component of the α-ketoglutarate dehydrogenase complex (OGDHC) whose loss reduces OGDHC activity, raising the α-ketoglutarate:citrate ratio and driving reductive carboxylation of glutamine-derived αKG, which activates mTORC1-dependent de novo lipogenesis [PMID:31899205]. Its catalytic role supports normal mitochondrial respiration, and loss-of-function impairs oxygen consumption in epithelial and neuronal cells [PMID:29669943, PMID:34800363]. Bi-allelic OGDHL variants cause a Mendelian neurodevelopmental disorder: pan-neuronal knockout of the Drosophila ortholog produces lethality and Krebs cycle defects rescued by wild-type cDNA, while human patient missense variants segregate into severe loss-of-function and hypomorphic alleles by complementation in fly and zebrafish models [PMID:34800363, PMID:38031187]. As a metabolic gatekeeper, OGDHL loss reprograms tumor metabolism along several axes: accumulation of L-2-hydroxyglutarate inhibits prolyl hydroxylases to stabilize HIF-1α and drive EMT and metastasis [PMID:36000493]; suppression by FTO-mediated m6A demethylation stabilizes TFAP2A to transcriptionally activate FASN and promote lipid accumulation and ERK signaling [PMID:37626053]; and forced expression elevates ROS to engage caspase-3, downregulating AKT and NF-κB signaling [PMID:23152800]. OGDHL physically interacts with PDHB, stabilizing it to sustain pyruvate oxidative decarboxylation and acetyl-CoA/ATP production [PMID:41420718]. An extra-mitochondrial role is also evident: in prostate cancer OGDHL supports nucleotide synthesis and neuroendocrine lineage plasticity independently of mitochondrial localization [PMID:41591383].","teleology":[{"year":2012,"claim":"Established that OGDHL can act as a tumor suppressor by linking its expression to a ROS-driven apoptotic signaling cascade, the first functional handle beyond presumed metabolic activity.","evidence":"Overexpression and shRNA knockdown in cervical cancer cells with ROS, caspase-3, and phospho-AKT/NF-κB readouts plus inhibitor rescue","pmids":["23152800"],"confidence":"Medium","gaps":["Mechanism connecting OGDHL enzymatic activity to ROS generation not defined","Single cancer cell context","No in vitro reconstitution of the proposed pathway"]},{"year":2018,"claim":"Demonstrated that OGDHL is required for normal mitochondrial respiration, grounding its cellular role in oxidative metabolism.","evidence":"shRNA knockdown in esophageal epithelial cells and patient fibroblasts with respirometry","pmids":["29669943"],"confidence":"Medium","gaps":["Limited mechanistic depth","Does not resolve which respiratory step is affected","Single lab"]},{"year":2019,"claim":"Defined the core metabolic consequence of OGDHL loss: reduced OGDHC activity raises the αKG:citrate ratio, driving reductive glutamine carboxylation and mTORC1-dependent lipogenesis.","evidence":"Overexpression/knockdown in hepatoma cells and xenografts with OGDHC activity assays, isotope tracing, metabolite profiling and pathway immunoblotting","pmids":["31899205"],"confidence":"High","gaps":["Direct enzymatic kinetics of OGDHL not characterized","Tissue specificity of the mTORC1 link unclear"]},{"year":2021,"claim":"Established OGDHL as a Mendelian neurodevelopmental disease gene and confirmed allele-specific severity through cross-species rescue.","evidence":"CRISPR knockout of Drosophila dOgdh with cDNA rescue, patient variant mutagenesis, and human neuronal knockout respirometry across multiple families","pmids":["34800363"],"confidence":"High","gaps":["Biochemical defect of individual variants not measured directly","Neuronal cell-type vulnerability not resolved"]},{"year":2021,"claim":"Probed whether OGDHL is neuroprotective in neurodegeneration models, linking it to Wnt/β-catenin signaling.","evidence":"OGDHL overexpression in 3×Tg-AD mice with histology, behavior, and Wnt7B expression in vitro","pmids":["34798170"],"confidence":"Low","gaps":["Single pathway marker per readout, mechanism not established","Causal link between OGDHL and Wnt signaling unproven","Not independently confirmed"]},{"year":2022,"claim":"Attempted to link a common OGDHL variant to brain glutamate accumulation via predicted cofactor-binding disruption.","evidence":"Whole-exome sequencing with computational conformational modeling of the transketolase domain and brain imaging","pmids":["35370858"],"confidence":"Low","gaps":["No in vitro validation of altered TPP binding","Causality between variant and phenotype not demonstrated","Mechanism purely computational"]},{"year":2023,"claim":"Connected OGDHL loss to oncogenic metabolic rewiring through distinct mechanisms: HIF-1α stabilization via L-2-HG and FASN induction via TFAP2A under FTO/m6A control.","evidence":"OGDHL OE/KD in HCC and ccRCC with L-2-HG measurement, HIF-1α stability assays, MeRIP, ChIP, luciferase, ubiquitination and in vivo metastasis models","pmids":["36000493","37626053"],"confidence":"Medium","gaps":["Each axis shown in a single cancer type","Direct demonstration that OGDHC activity loss produces L-2-HG not fully resolved","Single lab per mechanism"]},{"year":2023,"claim":"Clarified paralog compensation and allele-specific enzyme function among OGDHL, OGDH, and DHTKD1, refining genotype–phenotype interpretation.","evidence":"CRISPR zebrafish knockouts of ogdhl and paralogs with human patient-variant cDNA complementation and developmental phenotyping","pmids":["38031187"],"confidence":"Medium","gaps":["Degree of redundancy in human tissues unknown","Enzyme-level kinetics inferred, not directly measured"]},{"year":2025,"claim":"Identified PDHB as a direct physical partner of OGDHL, extending its influence to pyruvate oxidative decarboxylation.","evidence":"Co-IP in gastric cancer cells with PDHB stability, acetyl-CoA/ATP measurement and in vivo tumor models","pmids":["41420718"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation","Mechanism of PDHB stabilization undefined","Single cancer context"]},{"year":2025,"claim":"Revealed an extra-mitochondrial function for OGDHL in supporting nucleotide synthesis and neuroendocrine lineage plasticity, decoupling some roles from its canonical mitochondrial localization.","evidence":"OGDHL knockdown in prostate cancer cells and xenografts with nucleotide profiling, γH2AX, neuroendocrine markers, and mitochondrial localization mutant constructs","pmids":["41591383"],"confidence":"Medium","gaps":["Molecular basis of the extra-mitochondrial activity unknown","Direct biochemical substrate in this context not identified","Single lab"]},{"year":null,"claim":"How OGDHL is targeted to mitochondria versus retained for extra-mitochondrial functions, and the direct biochemical activity underlying its non-canonical roles, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of human OGDHL enzyme validated experimentally","Mechanism of subcellular partitioning unestablished","Direct kinetic characterization of OGDHL catalysis absent from the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,3]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,3,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,8]}],"complexes":["OGDHC (α-ketoglutarate dehydrogenase complex)"],"partners":["PDHB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULD0","full_name":"2-oxoglutarate dehydrogenase-like, mitochondrial","aliases":["2-oxoglutarate dehydrogenase complex component E1-like","OGDC-E1-like","Alpha-ketoglutarate dehydrogenase-like"],"length_aa":1010,"mass_kda":114.5,"function":"2-oxoglutarate dehydrogenase (E1-like) component of the 2-oxoglutarate dehydrogenase multienzyme complex (OGDHC) which mediates the decarboxylation of alpha-ketoglutarate in the tricarboxylic acid cycle. The OGDHC complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2) while reducing NAD(+) to NADH (By similarity). The OGDHC complex is mainly active in the mitochondrion (By similarity). Involved in the inhibition of cell proliferation and in apoptosis (PubMed:23152800, PubMed:31175094)","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/Q9ULD0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OGDHL","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OGDHL","total_profiled":1310},"omim":[{"mim_id":"619701","title":"YOON-BELLEN NEURODEVELOPMENTAL SYNDROME; YOBELN","url":"https://www.omim.org/entry/619701"},{"mim_id":"617513","title":"OXOGLUTARATE DEHYDROGENASE-LIKE PROTEIN; OGDHL","url":"https://www.omim.org/entry/617513"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":119.9},{"tissue":"kidney","ntpm":113.8},{"tissue":"liver","ntpm":74.8}],"url":"https://www.proteinatlas.org/search/OGDHL"},"hgnc":{"alias_symbol":["FLJ10851"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULD0","domains":[{"cath_id":"1.10.287.1150","chopping":"106-204","consensus_level":"high","plddt":87.0814,"start":106,"end":204},{"cath_id":"3.40.50.970","chopping":"236-572","consensus_level":"high","plddt":95.1582,"start":236,"end":572},{"cath_id":"3.40.50.12470","chopping":"599-769_818-861","consensus_level":"high","plddt":97.1601,"start":599,"end":861},{"cath_id":"3.40.50.11610","chopping":"872-1001","consensus_level":"high","plddt":96.0995,"start":872,"end":1001}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULD0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULD0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULD0-F1-predicted_aligned_error_v6.png","plddt_mean":90.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OGDHL","jax_strain_url":"https://www.jax.org/strain/search?query=OGDHL"},"sequence":{"accession":"Q9ULD0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULD0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULD0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULD0"}},"corpus_meta":[{"pmid":"31899205","id":"PMC_31899205","title":"OGDHL silencing promotes hepatocellular carcinoma by reprogramming glutamine metabolism.","date":"2019","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/31899205","citation_count":138,"is_preprint":false},{"pmid":"23152800","id":"PMC_23152800","title":"OGDHL is a modifier of AKT-dependent signaling and NF-κB function.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23152800","citation_count":67,"is_preprint":false},{"pmid":"32064152","id":"PMC_32064152","title":"miR-193a-5p promotes pancreatic cancer cell metastasis through SRSF6-mediated alternative splicing of OGDHL and ECM1.","date":"2020","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32064152","citation_count":53,"is_preprint":false},{"pmid":"29669943","id":"PMC_29669943","title":"Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis.","date":"2018","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/29669943","citation_count":46,"is_preprint":false},{"pmid":"37626050","id":"PMC_37626050","title":"The m6A modification-mediated OGDHL exerts a tumor suppressor role in ccRCC by downregulating FASN to inhibit lipid synthesis and ERK signaling.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37626050","citation_count":31,"is_preprint":false},{"pmid":"26299868","id":"PMC_26299868","title":"[Downregulation of OGDHL expression is associated with promoter hypermethylation in colorectal cancer].","date":"2015","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/26299868","citation_count":29,"is_preprint":false},{"pmid":"34800363","id":"PMC_34800363","title":"Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia.","date":"2021","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34800363","citation_count":25,"is_preprint":false},{"pmid":"36000493","id":"PMC_36000493","title":"Silencing of OGDHL promotes liver cancer metastasis by enhancing hypoxia inducible factor 1 α protein stability.","date":"2023","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/36000493","citation_count":15,"is_preprint":false},{"pmid":"30904169","id":"PMC_30904169","title":"Aberrant hypermethylation of OGDHL gene promoter in sporadic colorectal cancer.","date":"2019","source":"Current problems in cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30904169","citation_count":12,"is_preprint":false},{"pmid":"31837001","id":"PMC_31837001","title":"Discovery of rare coding variants in OGDHL and BRCA2 in relation to breast cancer risk in Chinese women.","date":"2019","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31837001","citation_count":12,"is_preprint":false},{"pmid":"38031187","id":"PMC_38031187","title":"Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity.","date":"2023","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38031187","citation_count":10,"is_preprint":false},{"pmid":"34798170","id":"PMC_34798170","title":"OGDHL ameliorates cognitive impairment and Alzheimer's disease-like pathology via activating Wnt/β-catenin signaling in Alzheimer's disease mice.","date":"2021","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/34798170","citation_count":9,"is_preprint":false},{"pmid":"35463769","id":"PMC_35463769","title":"The Potential of Metabolism-Related Gene OGDHL as a Biomarker for Myocardial Remodeling in Dilated Cardiomyopathy.","date":"2022","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35463769","citation_count":5,"is_preprint":false},{"pmid":"35370858","id":"PMC_35370858","title":"OGDHL Variant rs2293239: A Potential Genetic Driver of Chinese Familial Depressive Disorder.","date":"2022","source":"Frontiers in psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/35370858","citation_count":4,"is_preprint":false},{"pmid":"41463550","id":"PMC_41463550","title":"An Emerging Role for OGDHL: From Mitochondrial Energy Metabolism to Neurodevelopmental Disorders.","date":"2025","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41463550","citation_count":2,"is_preprint":false},{"pmid":"40579136","id":"PMC_40579136","title":"[Salidroside inhibits proliferation of gastric cancer cells by regulating the miR-1343-3p-OGDHL/PDHB glucose metabolic axis].","date":"2025","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/40579136","citation_count":2,"is_preprint":false},{"pmid":"40502162","id":"PMC_40502162","title":"OGDHL regulates tumor growth, neuroendocrine marker expression, and nucleotide abundance in prostate cancer.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40502162","citation_count":0,"is_preprint":false},{"pmid":"41591383","id":"PMC_41591383","title":"OGDHL Promotes Prostate Cancer Progression and Regulates Neuroendocrine Marker Expression and Nucleotide Abundance.","date":"2026","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/41591383","citation_count":0,"is_preprint":false},{"pmid":"41420718","id":"PMC_41420718","title":"miR-1343-3p regulating OGDHL/PDHB-pyruvate glucose metabolic reprogramming against gastric cancer cell proliferation.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41420718","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.11.648480","title":"DICAR-JP Regulates Ribosome Migration, a New Theory of Mitochondrial Protein Production","date":"2025-04-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.11.648480","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13682,"output_tokens":3376,"usd":0.045843,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11080,"output_tokens":3560,"usd":0.0722,"stage2_stop_reason":"end_turn"},"total_usd":0.118043,"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\": 2012,\n      \"finding\": \"Forced OGDHL expression in cervical cancer cells increased ROS production, leading to apoptosis through caspase-3-mediated downregulation of AKT signaling and decreased NF-κB phosphorylation; conversely, OGDHL knockdown increased AKT phosphorylation. Addition of caspase-3 or ROS inhibitors in the presence of OGDHL rescued AKT signaling and cell proliferation, placing OGDHL upstream of ROS→caspase-3→AKT/NF-κB.\",\n      \"method\": \"Overexpression and shRNA knockdown in cervical cancer cells; ROS measurement; caspase-3 activity; phospho-AKT and phospho-NF-κB immunoblotting; caspase/ROS inhibitor rescue experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal functional methods (OE + KD) with rescue experiments; single lab, no in vitro reconstitution\",\n      \"pmids\": [\"23152800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OGDHL downregulation reduced OGDH complex (OGDHC) activity, raising the α-ketoglutarate:citrate ratio and driving reductive carboxylation of glutamine-derived αKG via retrograde TCA cycling in hepatoma cells. Elevated αKG activated mTORC1 signaling, inducing transcription of de novo lipogenesis enzymes and providing NADPH/glutathione for antioxidant defense.\",\n      \"method\": \"OGDHL overexpression and knockdown in hepatoma cells and mouse xenografts; OGDHC activity assay; metabolite profiling (αKG:citrate ratio); isotope tracing of reductive glutamine carboxylation; mTORC1 pathway immunoblotting; lipogenesis enzyme expression analysis\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (enzymatic activity, metabolic tracing, in vivo xenograft, pathway immunoblotting) in one study with functional rescue\",\n      \"pmids\": [\"31899205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"shRNA-mediated disruption of OGDHL expression in esophageal epithelial cells blunted mitochondrial function (measured by oxygen consumption/respiration assays), establishing OGDHL as required for normal mitochondrial respiratory activity.\",\n      \"method\": \"shRNA knockdown in esophageal epithelial cells and patient fibroblasts; mitochondrial function assays (respirometry)\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function with mitochondrial functional readout; single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"29669943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pan-neuronal knockout of dOgdh (Drosophila ortholog of OGDHL) caused developmental lethality and defects in Krebs cycle metabolism rescued by wild-type dOgdh cDNA. Patient missense variants (p.Arg673Gln, p.Phe734Ser, p.Arg299Gly) behaved as severe loss-of-function alleles causing lethality, while others (p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, p.Arg244Trp) were hypomorphic. Human neuronal cells with OGDHL knockout showed defects in mitochondrial respiration.\",\n      \"method\": \"CRISPR-Cas9 tissue-specific knockout of dOgdh in Drosophila with cDNA rescue; Krebs cycle metabolite measurement; behavioral assays; OGDHL KO human neuronal cells with mitochondrial respirometry; splicing analysis of synonymous variant p.Val488Val in patient fibroblasts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution/rescue in Drosophila, mutagenesis across multiple alleles, human neuronal KO with respirometry, replicated across multiple families\",\n      \"pmids\": [\"34800363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FTO-mediated m6A demethylation suppressed OGDHL expression in clear cell renal cell carcinoma (ccRCC). Low OGDHL levels promoted TFAP2A expression by inhibiting its ubiquitination; TFAP2A then bound the FASN promoter to transcriptionally activate FASN, promoting lipid accumulation and ERK pathway activation.\",\n      \"method\": \"RNA methylation immunoprecipitation (MeRIP); luciferase reporter assays; chromatin immunoprecipitation (ChIP); mutagenesis; FTO overexpression/knockdown; ubiquitination assays; OGDHL OE/KD in vitro and in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MeRIP, ChIP, luciferase, mutagenesis, ubiquitination assay) in a single lab study\",\n      \"pmids\": [\"37626053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OGDHL silencing in HCC cells promoted accumulation of L-2-hydroxyglutarate (L-2-HG), which inhibited HIF-1α prolyl hydroxylases, stabilizing HIF-1α protein and enhancing its transactivation activity, thereby inducing epithelial-mesenchymal transition (EMT) and promoting metastasis.\",\n      \"method\": \"OGDHL overexpression and knockdown in HCC cells; in vivo metastasis models; L-2-HG metabolite measurement; HIF-1α protein stability assays; prolyl hydroxylase activity; EMT marker expression\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway established by metabolite measurement plus functional in vitro/in vivo assays; single lab\",\n      \"pmids\": [\"36000493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OGDHL overexpression in 3×Tg-AD mice reduced neuroinflammation, amyloid plaque load, and tau phosphorylation, and activated Wnt/β-catenin signaling (evidenced by increased Wnt7B expression) in vitro, linking OGDHL to neuroprotection via this pathway.\",\n      \"method\": \"OGDHL overexpression in 3×Tg-AD mice (Western blot, immunohistochemistry, qPCR); behavioral memory assays; Wnt7B expression in vitro\",\n      \"journal\": \"Behavioural brain research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vivo overexpression with pathway marker readout but limited mechanistic depth in the abstract; single lab, single method per pathway\",\n      \"pmids\": [\"34798170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A non-synonymous OGDHL variant rs2293239 (p.Asn725Ser) was predicted by computational modeling to cause a conformational change in the transketolase domain that reduces binding affinity for the cofactor thiamine pyrophosphate, resulting in abnormal glutamate accumulation in the brain.\",\n      \"method\": \"Whole-exome sequencing; structural/computational conformational analysis; brain imaging of variant carriers\",\n      \"journal\": \"Frontiers in psychiatry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — mechanism inferred from computational modeling with no in vitro biochemical validation of TPP binding\",\n      \"pmids\": [\"35370858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OGDHL and OGDH paralogs (OGDH, DHTKD1) exhibit complex transcriptional compensation and partial functional redundancy in zebrafish; ogdhl knockout zebrafish were rescued by human cDNA carrying various patient variants, with some alleles showing loss-of-function and others hypomorphic effects, indicating allele-specific functional differences at the enzyme level.\",\n      \"method\": \"CRISPR/Cas9 zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1; functional complementation with patient variant human cDNA transcripts; developmental phenotyping\",\n      \"journal\": \"Genome medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo CRISPR KO with cDNA rescue and multiple alleles tested; single lab but rigorous complementation design\",\n      \"pmids\": [\"38031187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Co-immunoprecipitation confirmed that OGDHL physically interacts with PDHB (pyruvate dehydrogenase E1-β subunit) in gastric cancer cells. Downregulation of OGDHL destabilized PDHB protein, reducing pyruvate oxidative decarboxylation and decreasing acetyl-CoA and ATP production.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP); si-OGDHL knockdown; PDHB protein stability assessment; acetyl-CoA and ATP measurement; in vivo tumor-bearing mouse models\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing physical interaction plus functional metabolic readouts; single lab\",\n      \"pmids\": [\"41420718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In prostate cancer cells, OGDHL loss impaired proliferation and reduced nucleotide synthesis, induced γH2AX (DNA damage marker) accumulation, and suppressed androgen receptor inhibition-induced neuroendocrine marker expression (DLL3, HES6). Crucially, mitochondrial localization of OGDHL was found to be dispensable for its regulation of nucleotide metabolism and lineage plasticity, suggesting an extra-mitochondrial function.\",\n      \"method\": \"OGDHL knockdown in prostate cancer cell lines and xenografts; nucleotide abundance measurement; γH2AX immunoblotting; neuroendocrine marker expression; mitochondrial localization mutant constructs\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal readouts including localization mutant; single lab\",\n      \"pmids\": [\"41591383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DICAR-JP (a peptide sequence) interacted with NACα (nascent polypeptide-associated complex alpha) to regulate OGDHL nascent peptide expression and facilitate translocation of OGDHL from cytoplasmic ribosomes to mitochondria, as measured by in vitro translation and SPR binding assays.\",\n      \"method\": \"Surface plasmon resonance (SPR) for DICAR-JP/NACα binding; in vitro translation assay; biotin-DICAR-JP pulldown; untargeted metabolomics; AAV9-mediated overexpression in db/db mice\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, novel mechanistic claim (ribosome migration) not yet peer-reviewed; SPR and in vitro translation support interaction but full validation absent\",\n      \"pmids\": [\"40502162\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"OGDHL is a brain-enriched, rate-limiting component of the α-ketoglutarate dehydrogenase complex (OGDHC) that catalyzes a key step in the TCA cycle; its loss reduces OGDHC activity, elevates the αKG:citrate ratio, drives reductive glutamine carboxylation, activates mTORC1-dependent lipogenesis, stabilizes HIF-1α via L-2-HG accumulation, and suppresses AKT/NF-κB signaling through ROS–caspase-3, while bi-allelic loss-of-function variants cause a Mendelian neurodevelopmental disorder characterized by epilepsy, hearing loss, and mitochondrial respiratory defects; in prostate cancer, OGDHL paradoxically supports nucleotide synthesis and neuroendocrine lineage plasticity independently of mitochondrial localization, and it physically interacts with PDHB to regulate pyruvate metabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OGDHL is a rate-limiting component of the α-ketoglutarate dehydrogenase complex (OGDHC) whose loss reduces OGDHC activity, raising the α-ketoglutarate:citrate ratio and driving reductive carboxylation of glutamine-derived αKG, which activates mTORC1-dependent de novo lipogenesis [#1]. Its catalytic role supports normal mitochondrial respiration, and loss-of-function impairs oxygen consumption in epithelial and neuronal cells [#2, #3]. Bi-allelic OGDHL variants cause a Mendelian neurodevelopmental disorder: pan-neuronal knockout of the Drosophila ortholog produces lethality and Krebs cycle defects rescued by wild-type cDNA, while human patient missense variants segregate into severe loss-of-function and hypomorphic alleles by complementation in fly and zebrafish models [#3, #8]. As a metabolic gatekeeper, OGDHL loss reprograms tumor metabolism along several axes: accumulation of L-2-hydroxyglutarate inhibits prolyl hydroxylases to stabilize HIF-1α and drive EMT and metastasis [#5]; suppression by FTO-mediated m6A demethylation stabilizes TFAP2A to transcriptionally activate FASN and promote lipid accumulation and ERK signaling [#4]; and forced expression elevates ROS to engage caspase-3, downregulating AKT and NF-κB signaling [#0]. OGDHL physically interacts with PDHB, stabilizing it to sustain pyruvate oxidative decarboxylation and acetyl-CoA/ATP production [#9]. An extra-mitochondrial role is also evident: in prostate cancer OGDHL supports nucleotide synthesis and neuroendocrine lineage plasticity independently of mitochondrial localization [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that OGDHL can act as a tumor suppressor by linking its expression to a ROS-driven apoptotic signaling cascade, the first functional handle beyond presumed metabolic activity.\",\n      \"evidence\": \"Overexpression and shRNA knockdown in cervical cancer cells with ROS, caspase-3, and phospho-AKT/NF-κB readouts plus inhibitor rescue\",\n      \"pmids\": [\"23152800\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism connecting OGDHL enzymatic activity to ROS generation not defined\", \"Single cancer cell context\", \"No in vitro reconstitution of the proposed pathway\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that OGDHL is required for normal mitochondrial respiration, grounding its cellular role in oxidative metabolism.\",\n      \"evidence\": \"shRNA knockdown in esophageal epithelial cells and patient fibroblasts with respirometry\",\n      \"pmids\": [\"29669943\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Limited mechanistic depth\", \"Does not resolve which respiratory step is affected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the core metabolic consequence of OGDHL loss: reduced OGDHC activity raises the αKG:citrate ratio, driving reductive glutamine carboxylation and mTORC1-dependent lipogenesis.\",\n      \"evidence\": \"Overexpression/knockdown in hepatoma cells and xenografts with OGDHC activity assays, isotope tracing, metabolite profiling and pathway immunoblotting\",\n      \"pmids\": [\"31899205\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct enzymatic kinetics of OGDHL not characterized\", \"Tissue specificity of the mTORC1 link unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established OGDHL as a Mendelian neurodevelopmental disease gene and confirmed allele-specific severity through cross-species rescue.\",\n      \"evidence\": \"CRISPR knockout of Drosophila dOgdh with cDNA rescue, patient variant mutagenesis, and human neuronal knockout respirometry across multiple families\",\n      \"pmids\": [\"34800363\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Biochemical defect of individual variants not measured directly\", \"Neuronal cell-type vulnerability not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Probed whether OGDHL is neuroprotective in neurodegeneration models, linking it to Wnt/β-catenin signaling.\",\n      \"evidence\": \"OGDHL overexpression in 3×Tg-AD mice with histology, behavior, and Wnt7B expression in vitro\",\n      \"pmids\": [\"34798170\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single pathway marker per readout, mechanism not established\", \"Causal link between OGDHL and Wnt signaling unproven\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Attempted to link a common OGDHL variant to brain glutamate accumulation via predicted cofactor-binding disruption.\",\n      \"evidence\": \"Whole-exome sequencing with computational conformational modeling of the transketolase domain and brain imaging\",\n      \"pmids\": [\"35370858\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No in vitro validation of altered TPP binding\", \"Causality between variant and phenotype not demonstrated\", \"Mechanism purely computational\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected OGDHL loss to oncogenic metabolic rewiring through distinct mechanisms: HIF-1α stabilization via L-2-HG and FASN induction via TFAP2A under FTO/m6A control.\",\n      \"evidence\": \"OGDHL OE/KD in HCC and ccRCC with L-2-HG measurement, HIF-1α stability assays, MeRIP, ChIP, luciferase, ubiquitination and in vivo metastasis models\",\n      \"pmids\": [\"36000493\", \"37626053\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Each axis shown in a single cancer type\", \"Direct demonstration that OGDHC activity loss produces L-2-HG not fully resolved\", \"Single lab per mechanism\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Clarified paralog compensation and allele-specific enzyme function among OGDHL, OGDH, and DHTKD1, refining genotype–phenotype interpretation.\",\n      \"evidence\": \"CRISPR zebrafish knockouts of ogdhl and paralogs with human patient-variant cDNA complementation and developmental phenotyping\",\n      \"pmids\": [\"38031187\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Degree of redundancy in human tissues unknown\", \"Enzyme-level kinetics inferred, not directly measured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified PDHB as a direct physical partner of OGDHL, extending its influence to pyruvate oxidative decarboxylation.\",\n      \"evidence\": \"Co-IP in gastric cancer cells with PDHB stability, acetyl-CoA/ATP measurement and in vivo tumor models\",\n      \"pmids\": [\"41420718\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Mechanism of PDHB stabilization undefined\", \"Single cancer context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed an extra-mitochondrial function for OGDHL in supporting nucleotide synthesis and neuroendocrine lineage plasticity, decoupling some roles from its canonical mitochondrial localization.\",\n      \"evidence\": \"OGDHL knockdown in prostate cancer cells and xenografts with nucleotide profiling, γH2AX, neuroendocrine markers, and mitochondrial localization mutant constructs\",\n      \"pmids\": [\"41591383\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular basis of the extra-mitochondrial activity unknown\", \"Direct biochemical substrate in this context not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OGDHL is targeted to mitochondria versus retained for extra-mitochondrial functions, and the direct biochemical activity underlying its non-canonical roles, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of human OGDHL enzyme validated experimentally\", \"Mechanism of subcellular partitioning unestablished\", \"Direct kinetic characterization of OGDHL catalysis absent from the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 3, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"complexes\": [\"OGDHC (α-ketoglutarate dehydrogenase complex)\"],\n    \"partners\": [\"PDHB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"OGDHL","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"medium","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 37626053"},"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}