{"gene":"DLST","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1990,"finding":"KGD2 (yeast ortholog of DLST) encodes the dihydrolipoyl transsuccinylase (E2) component of the α-ketoglutarate dehydrogenase complex; chromosomal disruption of KGD2 abolished the ability of mitochondria to catalyze NAD+ reduction by α-ketoglutarate, establishing its essential catalytic role in the complex.","method":"Gene disruption (chromosomal KGD2 knockout), biochemical complementation assay, sequence analysis showing 42% identity to E. coli KE2","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — gene disruption with direct biochemical readout (loss of complex activity), replicated across multiple mutant strains, sequence-function correlation","pmids":["2115121"],"is_preprint":false},{"year":1990,"finding":"KGD2 transcription is activated by the HAP2 and HAP3 proteins via upstream sequence elements (244–484 nt upstream of the structural gene) containing HAP consensus cores, as shown by lacZ fusion assays in hap2 and hap3 mutant strains.","method":"lacZ promoter fusion assay, deletion analysis, Northern blot in wild-type vs. hap2/hap3 mutants","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (lacZ fusions, deletion mapping, Northern blot) in the same study with genetic controls","pmids":["2115121"],"is_preprint":false},{"year":2003,"finding":"The DLST gene is bifunctional: in addition to encoding the full-length mitochondrial E2 subunit, it produces a truncated protein (MIRTD) from an internal transcript starting in intron 7. MIRTD localizes to the mitochondrial intermembrane space and is required post-translationally for the stability/biogenesis of mitochondrial respiratory chain complexes I and IV.","method":"Novel mRNA cloning/sequencing, immunocytochemical localization, maxizyme (ribozyme)-mediated specific knockdown of MIRTD mRNA in SH-SY5Y cells, pulse-label experiment, measurement of respiratory complex subunit levels and activity","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — specific mRNA knockdown with multiple functional readouts (respiratory complex subunit levels, complex activity, pulse-label showing post-translational loss) in a single rigorous study","pmids":["12805207"],"is_preprint":false},{"year":2009,"finding":"The DLST gene undergoes alternative splicing (deletion of exons 2 and 3, or exon 2, or exon 3) to produce a ~30 kDa protein that localizes to the I bands of myofibrils in rat skeletal muscle, distinct from the mitochondrial full-length DLST protein.","method":"Anti-DLST antibody immunocytochemical staining, protein purification and amino acid sequencing, cDNA isolation and sequencing of splicing variants","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein purification with sequence confirmation and immunolocalization, single lab, two orthogonal methods","pmids":["19819302"],"is_preprint":false},{"year":2015,"finding":"Loss of DLST function in zebrafish (schneckentempo mutant) causes severely reduced resting heart rate due to defective excitation generation in cardiac pacemaker cells; ATP levels are significantly diminished in mutant embryos, linking DLST-dependent TCA cycle activity to cardiac pacemaker energy supply.","method":"Positional cloning, gene knockdown (morpholino), external electrical pacing, ATP level measurement in mutant embryos","journal":"Basic research in cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — positional cloning combined with gene knockdown confirmation, functional electrophysiological rescue experiment, direct ATP measurement establishing mechanism","pmids":["25697682"],"is_preprint":false},{"year":2016,"finding":"DLST (E2 transferase of α-KG dehydrogenase complex) is required for TCA cycle flux in T-ALL cells: RNAi knockdown causes accumulation of α-KG and decrease of succinyl-CoA, reduces cell viability, and induces apoptosis; addition of succinate (downstream TCA intermediate) rescues viability defects caused by DLST inactivation.","method":"RNAi knockdown, polar metabolomics profiling, cell viability assay, apoptosis assay, metabolite rescue experiment, zebrafish genetic model (heterozygous dlst inactivation delaying tumor onset)","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — metabolomics profiling of specific TCA substrates/products, genetic epistasis in zebrafish, metabolite rescue establishing pathway position, multiple orthogonal methods","pmids":["26876595"],"is_preprint":false},{"year":2019,"finding":"Germline DLST variant p.Gly374Glu triggers accumulation of 2-hydroxyglutarate in tumors and in a heterologous cell-based functional assay, linking impaired DLST activity to oncometabolite production and pseudohypoxia-related epigenetic profiles in pheochromocytoma-paraganglioma.","method":"Targeted sequencing, 13C5-glutamate labeling assay, TCA-related metabolite determination, omics-based methylation/expression profiling, heterologous cell-based functional assay for DLST variants","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — 13C isotope tracing plus cell-based functional assay plus omics profiling, multiple orthogonal methods in a single rigorous study","pmids":["30929736"],"is_preprint":false},{"year":2021,"finding":"DLST loss in MYCN-amplified neuroblastoma cells suppresses NADH production and impairs oxidative phosphorylation (OXPHOS) without significantly altering TCA cycle metabolites other than α-KG accumulation, leading to growth arrest and apoptosis; monoallelic dlst loss in zebrafish impedes MYCN-driven tumor initiation.","method":"RNAi/shRNA depletion, NADH measurement, OXPHOS functional assays, metabolomics, zebrafish tumor model with dlst heterozygous loss, mouse xenograft model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (metabolomics, NADH/OXPHOS measurement, in vivo zebrafish and mouse models) from a single rigorous study","pmids":["34233924"],"is_preprint":false},{"year":2021,"finding":"DLST depletion in DLST-dependent TNBC cells significantly alters TCA cycle metabolites and reactive oxygen species (ROS)-related pathways; DLST depletion increases ROS levels and N-acetyl-L-cysteine partially rescues cell growth, establishing a mechanistic link between DLST-mediated TCA activity and ROS homeostasis in these cancer cells.","method":"RNAi knockdown, metabolomics profiling, ROS level measurement, N-acetyl-L-cysteine rescue experiment, invasion assay","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (metabolomics, ROS assay, antioxidant rescue) in single lab","pmids":["34785772"],"is_preprint":false},{"year":2021,"finding":"Germline DLST variants (p.Pro384Leu and p.Gly374Glu combined with somatic p.Thr383Ala) profoundly impact enzyme activity and result in DNA hypermethylation in pheochromocytoma-paraganglioma, as shown by functional assays on patient tumor material and engineered cell lines.","method":"In silico and functional enzyme activity assays, DNA methylation profiling, engineered cell lines expressing DLST variants","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional enzyme assay plus epigenetic readout in engineered cell lines, single lab","pmids":["33180916"],"is_preprint":false},{"year":2023,"finding":"Grpel2 (a mitochondrial nucleotide exchange factor) physically interacts with DLST and positively mediates the import of DLST into mitochondria under high-glucose conditions; siRNA knockdown of DLST abolishes Grpel2-mediated protection of mitochondrial function and cardiomyocyte survival in diabetic cardiomyopathy.","method":"Co-immunoprecipitation (Co-IP), siRNA knockdown of DLST, mitochondrial ROS measurement, mitochondrial respiratory capacity assay, mitochondrial membrane potential assay, AAV9 overexpression in mouse model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP establishing interaction, functional rescue by DLST siRNA, multiple mitochondrial functional readouts, single lab","pmids":["36927450"],"is_preprint":false},{"year":2024,"finding":"EPC1/2 regulate DLST expression via histone H3 acetylation at the DLST locus, acting cooperatively with transcription factors SRF and FOXR2; this EPC1/2–H3 acetylation–DLST axis is required for hematopoietic stem and progenitor cell (HSPC) emergence and proliferation.","method":"EPC1/2 depletion in zebrafish model, ChIP (H3 acetylation at DLST locus), HSPC quantification, K562 cell gene expression profiling","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating H3 acetylation at DLST locus, genetic depletion with HSPC phenotypic readout, single lab","pmids":["38439957"],"is_preprint":false},{"year":2025,"finding":"The lncRNA APCDD1L-AS1, transcriptionally activated by HIF-1α under hypoxia, forms a complex with DLST and inhibits its ubiquitination and degradation, thereby stabilizing DLST protein and driving TCA cycle activity to promote osimertinib resistance in lung adenocarcinoma.","method":"Co-IP (APCDD1L-AS1–DLST complex), ubiquitination assay, lncRNA knockdown/overexpression, ChIP (HIF-1α binding to APCDD1L-AS1 promoter), in vitro and in vivo resistance models","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing complex formation, ubiquitination assay demonstrating DLST stabilization mechanism, in vivo validation, single lab","pmids":["40634956"],"is_preprint":false},{"year":2026,"finding":"DLST knockdown in osteosarcoma cells suppresses proliferation, migration, invasion, and promotes apoptosis; RNA-seq and pathway inhibitor experiments place DLST upstream of the p38 MAPK signaling pathway, with a p38 MAPK inhibitor reversing the malignant functional changes caused by DLST knockdown.","method":"siRNA knockdown, RNA-seq, pharmacological p38 MAPK inhibition (functional rescue), CCK-8, colony formation, scratch, transwell assays, animal tumor model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq pathway analysis combined with pharmacological rescue epistasis and in vivo validation, single lab","pmids":["41616466"],"is_preprint":false},{"year":2025,"finding":"Under glutamine deficiency, DLST (along with OGDH) relocalizes to the nucleus in muscle progenitor cells, where increased nuclear TCA enzyme presence correlates with elevated histone succinylation and reduced chromatin accessibility at the MyoD1 locus, impairing myogenesis.","method":"Confocal imaging of nuclear localization, succinyl-proteomics, single-cell nuclei ATAC sequencing, glutamine depletion experiments in human primary myoblasts (HSKM2) and C2C12 cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, localization data and epigenetic correlation without direct functional manipulation of DLST specifically","pmids":[],"is_preprint":true}],"current_model":"DLST encodes the E2 dihydrolipoyl succinyltransferase core component of the α-ketoglutarate dehydrogenase complex (KGDHC), catalyzing the conversion of α-KG to succinyl-CoA in the TCA cycle to generate NADH for OXPHOS; it is imported into the mitochondrial matrix (assisted by Grpel2), regulated transcriptionally by histone H3 acetylation via EPC1/2 and by catabolite repression via HAP2/HAP3 (yeast), and its activity is required for NADH/ATP production, ROS homeostasis, and downstream MAPK signaling, while pathogenic variants impair enzyme activity leading to 2-hydroxyglutarate accumulation and DNA hypermethylation; the gene is also bifunctional, producing a truncated intermembrane-space protein (MIRTD) required for respiratory complex I and IV biogenesis, and alternative splicing generates a myofibrillar I-band isoform."},"narrative":{"mechanistic_narrative":"DLST encodes the dihydrolipoyl succinyltransferase (E2) core component of the α-ketoglutarate dehydrogenase complex, catalyzing conversion of α-ketoglutarate to succinyl-CoA in the TCA cycle; disruption of its yeast ortholog KGD2 abolishes mitochondrial NAD+ reduction by α-ketoglutarate, establishing its essential catalytic role [PMID:2115121]. Through this activity DLST controls TCA flux and the downstream supply of NADH for oxidative phosphorylation: depletion arrests TCA cycle progression with α-KG accumulation and loss of succinyl-CoA, and the resulting energetic and metabolic defects drive apoptosis that is rescued by downstream intermediates such as succinate [PMID:26876595, PMID:34233924]. This DLST-dependent energy supply is physiologically required, exemplified by defective cardiac pacemaker excitation and reduced ATP in DLST-deficient zebrafish [PMID:25697682]. In cancer contexts DLST is a metabolic dependency: it sustains NADH/OXPHOS and proliferation in MYCN-amplified neuroblastoma and T-ALL [PMID:26876595, PMID:34233924], regulates ROS homeostasis in triple-negative breast cancer [PMID:34785772], and acts upstream of p38 MAPK signaling in osteosarcoma [PMID:41616466]. Pathogenic germline DLST variants impair enzyme activity and cause accumulation of the oncometabolite 2-hydroxyglutarate with attendant DNA hypermethylation in pheochromocytoma-paraganglioma [PMID:30929736, PMID:33180916]. DLST levels are set both transcriptionally, through EPC1/2-mediated histone H3 acetylation acting with SRF and FOXR2 to drive hematopoietic progenitor emergence [PMID:38439957], and post-translationally, through Grpel2-assisted mitochondrial import [PMID:36927450] and lncRNA-mediated protection from ubiquitin-dependent degradation [PMID:40634956]. The DLST locus is bifunctional, additionally producing a truncated intermembrane-space protein (MIRTD) required for biogenesis of respiratory complexes I and IV [PMID:12805207], and alternative splicing yields a ~30 kDa myofibrillar I-band isoform [PMID:19819302].","teleology":[{"year":1990,"claim":"Established that DLST's ortholog is the catalytic E2 subunit of the α-ketoglutarate dehydrogenase complex and is indispensable for complex activity, defining its core biochemical function.","evidence":"Chromosomal KGD2 disruption with biochemical complementation assay and sequence analysis in yeast","pmids":["2115121"],"confidence":"High","gaps":["Performed in yeast ortholog, not human DLST","Structural basis of catalysis not resolved","Regulation of complex assembly not addressed"]},{"year":1990,"claim":"Showed the gene's transcription is under nutrient/catabolite control via HAP2/HAP3 activators, linking expression to respiratory metabolic demand.","evidence":"lacZ promoter fusions, deletion mapping, and Northern blot in hap2/hap3 mutant yeast","pmids":["2115121"],"confidence":"High","gaps":["HAP-element regulation demonstrated only in yeast","Human transcriptional control not addressed here"]},{"year":2003,"claim":"Revealed the DLST locus is bifunctional, encoding a distinct intermembrane-space protein (MIRTD) needed for respiratory complex I and IV biogenesis beyond the matrix E2 enzyme.","evidence":"Novel transcript cloning, immunolocalization, and maxizyme-mediated MIRTD knockdown with respiratory complex readouts in SH-SY5Y cells","pmids":["12805207"],"confidence":"High","gaps":["Molecular mechanism by which MIRTD supports complex assembly unknown","Interaction partners of MIRTD not identified"]},{"year":2009,"claim":"Identified a non-mitochondrial myofibrillar I-band isoform produced by alternative splicing, indicating tissue-specific functional diversification.","evidence":"Immunocytochemistry, protein purification with sequencing, and cDNA isolation of splice variants in rat skeletal muscle","pmids":["19819302"],"confidence":"Medium","gaps":["Function of the I-band isoform unknown","Demonstrated in rat only","No catalytic or structural role established"]},{"year":2015,"claim":"Connected DLST-dependent TCA activity to organ physiology by showing its loss reduces ATP and impairs cardiac pacemaker excitation.","evidence":"Positional cloning, morpholino knockdown, electrical pacing rescue, and ATP measurement in zebrafish embryos","pmids":["25697682"],"confidence":"High","gaps":["Mechanism linking ATP deficit to pacemaker excitation not fully resolved","Tissue-specific dependency not dissected"]},{"year":2016,"claim":"Placed DLST as a metabolic dependency in cancer, defining its pathway position via metabolite epistasis where downstream succinate rescues loss-of-function.","evidence":"RNAi, polar metabolomics, viability/apoptosis assays, metabolite rescue, and zebrafish genetic model in T-ALL","pmids":["26876595"],"confidence":"High","gaps":["Selectivity of T-ALL dependence vs normal cells not fully defined","Mechanism of apoptosis induction not specified"]},{"year":2019,"claim":"Linked impaired DLST enzyme function to oncometabolite (2-hydroxyglutarate) accumulation and pseudohypoxic epigenetic reprogramming in hereditary tumors.","evidence":"Targeted sequencing, 13C5-glutamate tracing, metabolite and methylation/expression profiling, and heterologous functional assay in pheochromocytoma-paraganglioma","pmids":["30929736"],"confidence":"High","gaps":["Enzymatic route from DLST deficiency to 2-HG production not mechanistically detailed","Causality of methylation changes for tumorigenesis not proven"]},{"year":2021,"claim":"Distinguished DLST's primary cancer-relevant output as NADH/OXPHOS support rather than broad TCA metabolite supply in MYCN-amplified neuroblastoma.","evidence":"shRNA depletion, NADH and OXPHOS assays, metabolomics, zebrafish and mouse xenograft tumor models","pmids":["34233924"],"confidence":"High","gaps":["Why only α-KG accumulates among TCA intermediates unexplained","Generality across non-MYCN tumors not tested"]},{"year":2021,"claim":"Established DLST control of ROS homeostasis as a determinant of cancer cell growth, with antioxidant rescue defining the link.","evidence":"RNAi, metabolomics, ROS measurement, and N-acetyl-L-cysteine rescue in triple-negative breast cancer cells","pmids":["34785772"],"confidence":"Medium","gaps":["Source of elevated ROS upon DLST loss not pinpointed","Partial rescue indicates additional mechanisms"]},{"year":2021,"claim":"Confirmed specific germline DLST variants directly reduce enzyme activity and drive DNA hypermethylation in patient-derived and engineered systems.","evidence":"Functional enzyme activity assays, DNA methylation profiling, and engineered variant cell lines","pmids":["33180916"],"confidence":"Medium","gaps":["Single lab","Mechanistic chain from activity loss to methylation not fully reconstituted"]},{"year":2023,"claim":"Identified Grpel2 as a physical partner mediating glucose-dependent mitochondrial import of DLST, coupling import to cardiomyocyte protection.","evidence":"Reciprocal Co-IP, DLST siRNA, mitochondrial ROS/respiration/membrane potential assays, and AAV9 mouse model of diabetic cardiomyopathy","pmids":["36927450"],"confidence":"Medium","gaps":["Direct vs indirect Grpel2-DLST contact not structurally resolved","Single lab"]},{"year":2024,"claim":"Defined an EPC1/2–histone H3 acetylation axis that transcriptionally activates DLST with SRF and FOXR2 to support hematopoietic stem and progenitor emergence.","evidence":"EPC1/2 depletion, ChIP for H3 acetylation at the DLST locus, HSPC quantification in zebrafish, and K562 expression profiling","pmids":["38439957"],"confidence":"Medium","gaps":["Direct binding of SRF/FOXR2 to DLST regulatory regions not fully mapped","Whether DLST metabolic output mediates HSPC effect not proven"]},{"year":2025,"claim":"Revealed post-translational stabilization of DLST by a HIF-1α-induced lncRNA that blocks its ubiquitination, coupling hypoxia to DLST-driven therapy resistance.","evidence":"Co-IP of APCDD1L-AS1–DLST complex, ubiquitination assay, lncRNA knockdown/overexpression, HIF-1α ChIP, and in vivo resistance models in lung adenocarcinoma","pmids":["40634956"],"confidence":"Medium","gaps":["E3 ligase targeting DLST not identified","Single lab"]},{"year":2026,"claim":"Positioned DLST upstream of p38 MAPK signaling as the route by which it promotes osteosarcoma malignancy.","evidence":"siRNA knockdown, RNA-seq, pharmacological p38 MAPK inhibition rescue, migration/invasion assays, and animal tumor model","pmids":["41616466"],"confidence":"Medium","gaps":["Molecular connection between DLST metabolism and p38 activation unknown","Single lab"]},{"year":null,"claim":"Whether DLST has a moonlighting nuclear, chromatin-modifying role via histone succinylation remains to be functionally established.","evidence":"Nuclear relocalization and succinyl-proteomics correlation under glutamine deficiency in myoblasts (preprint), without direct DLST manipulation","pmids":[],"confidence":"Low","gaps":["Preprint, not peer-reviewed","No direct functional manipulation of DLST tying nuclear localization to histone succinylation","Causality for myogenesis impairment not demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,5,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,9]}],"complexes":["α-ketoglutarate dehydrogenase complex (KGDHC)"],"partners":["GRPEL2","EPC1","EPC2","OGDH","APCDD1L-AS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P36957","full_name":"Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial","aliases":["2-oxoglutarate dehydrogenase complex component E2","OGDC-E2","Dihydrolipoamide succinyltransferase component of 2-oxoglutarate dehydrogenase complex","E2K"],"length_aa":453,"mass_kda":48.8,"function":"Dihydrolipoamide succinyltransferase (E2) component of the 2-oxoglutarate dehydrogenase complex. The 2-oxoglutarate dehydrogenase complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). The 2-oxoglutarate dehydrogenase complex is mainly active in the mitochondrion (PubMed:29211711, PubMed:30929736). 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 matrix; Nucleus","url":"https://www.uniprot.org/uniprotkb/P36957/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DLST","classification":"Not Classified","n_dependent_lines":375,"n_total_lines":1208,"dependency_fraction":0.31043046357615894},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DLST","total_profiled":1310},"omim":[{"mim_id":"618475","title":"PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 7; PPGL7","url":"https://www.omim.org/entry/618475"},{"mim_id":"613022","title":"OXOGLUTARATE DEHYDROGENASE; OGDH","url":"https://www.omim.org/entry/613022"},{"mim_id":"610284","title":"LIPOYLTRANSFERASE 1; LIPT1","url":"https://www.omim.org/entry/610284"},{"mim_id":"168000","title":"PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1; PPGL1","url":"https://www.omim.org/entry/168000"},{"mim_id":"126063","title":"DIHYDROLIPOAMIDE S-SUCCINYLTRANSFERASE; DLST","url":"https://www.omim.org/entry/126063"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Mitochondria","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DLST"},"hgnc":{"alias_symbol":["OGDC-E2","KGD2"],"prev_symbol":["DLTS"]},"alphafold":{"accession":"P36957","domains":[{"cath_id":"2.40.50.100","chopping":"70-144","consensus_level":"high","plddt":82.7177,"start":70,"end":144},{"cath_id":"3.30.559.10","chopping":"232-450","consensus_level":"high","plddt":94.0127,"start":232,"end":450}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P36957","model_url":"https://alphafold.ebi.ac.uk/files/AF-P36957-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P36957-F1-predicted_aligned_error_v6.png","plddt_mean":76.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DLST","jax_strain_url":"https://www.jax.org/strain/search?query=DLST"},"sequence":{"accession":"P36957","fasta_url":"https://rest.uniprot.org/uniprotkb/P36957.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P36957/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P36957"}},"corpus_meta":[{"pmid":"2115121","id":"PMC_2115121","title":"Structure and regulation of KGD2, the structural gene for yeast dihydrolipoyl transsuccinylase.","date":"1990","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2115121","citation_count":55,"is_preprint":false},{"pmid":"34233924","id":"PMC_34233924","title":"Metabolic Enzyme DLST Promotes Tumor Aggression and Reveals a Vulnerability to OXPHOS Inhibition in High-Risk Neuroblastoma.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/34233924","citation_count":52,"is_preprint":false},{"pmid":"26876595","id":"PMC_26876595","title":"The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis.","date":"2016","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/26876595","citation_count":51,"is_preprint":false},{"pmid":"34785772","id":"PMC_34785772","title":"DLST-dependence dictates metabolic heterogeneity in TCA-cycle usage among triple-negative breast cancer.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/34785772","citation_count":50,"is_preprint":false},{"pmid":"30929736","id":"PMC_30929736","title":"Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas.","date":"2019","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30929736","citation_count":49,"is_preprint":false},{"pmid":"9894876","id":"PMC_9894876","title":"Modulation by DLST of the genetic risk of Alzheimer's disease in a very elderly population.","date":"1999","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/9894876","citation_count":35,"is_preprint":false},{"pmid":"25697682","id":"PMC_25697682","title":"Loss of dihydrolipoyl succinyltransferase (DLST) leads to reduced resting heart rate in the zebrafish.","date":"2015","source":"Basic research in cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/25697682","citation_count":26,"is_preprint":false},{"pmid":"12805207","id":"PMC_12805207","title":"Truncated product of the bifunctional DLST gene involved in biogenesis of the respiratory chain.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12805207","citation_count":24,"is_preprint":false},{"pmid":"10227647","id":"PMC_10227647","title":"A DLST genotype associated with reduced risk for Alzheimer's disease.","date":"1999","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10227647","citation_count":24,"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":"12753811","id":"PMC_12753811","title":"Promiscuous T cells selected by Escherichia coli: OGDC-E2 in primary biliary cirrhosis.","date":"2003","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/12753811","citation_count":17,"is_preprint":false},{"pmid":"19832717","id":"PMC_19832717","title":"Usefulness of double locus sequence typing (DLST) for regional and international epidemiological surveillance of methicilin-resistant Staphylococcus aureus.","date":"2009","source":"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19832717","citation_count":17,"is_preprint":false},{"pmid":"8584231","id":"PMC_8584231","title":"Mutation analysis of the chromosome 14q24.3 dihydrolipoyl succinyltransferase (DLST) gene in patients with early-onset Alzheimer disease.","date":"1995","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/8584231","citation_count":11,"is_preprint":false},{"pmid":"11445257","id":"PMC_11445257","title":"No association between DLST gene and Alzheimer's disease or Wernicke-Korsakoff syndrome.","date":"2001","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/11445257","citation_count":11,"is_preprint":false},{"pmid":"33180916","id":"PMC_33180916","title":"Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma.","date":"2021","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/33180916","citation_count":9,"is_preprint":false},{"pmid":"36927450","id":"PMC_36927450","title":"Grpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through DLST-mediated mitochondrial dysfunction: a proof-of-concept study.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36927450","citation_count":8,"is_preprint":false},{"pmid":"38439957","id":"PMC_38439957","title":"EPC1/2 regulate hematopoietic stem and progenitor cell proliferation by modulating H3 acetylation and DLST.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38439957","citation_count":7,"is_preprint":false},{"pmid":"37506369","id":"PMC_37506369","title":"MYOD induced lnc-MEG3 promotes porcine satellite cell differentiation via interacting with DLST.","date":"2023","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/37506369","citation_count":7,"is_preprint":false},{"pmid":"31087708","id":"PMC_31087708","title":"Rno-miR-425-5p targets the DLST and SLC16A1 genes to reduce liver damage caused by excessive energy mobilization under cold stress.","date":"2019","source":"Journal of animal physiology and animal nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/31087708","citation_count":7,"is_preprint":false},{"pmid":"16531715","id":"PMC_16531715","title":"[DLST as a method for detecting TS-1-induced allergy].","date":"2006","source":"Gan to kagaku ryoho. Cancer & chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/16531715","citation_count":7,"is_preprint":false},{"pmid":"30214536","id":"PMC_30214536","title":"Association of OGG1 and DLST promoter methylation with Alzheimer's disease in Xinjiang population.","date":"2018","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30214536","citation_count":4,"is_preprint":false},{"pmid":"40634956","id":"PMC_40634956","title":"Hypoxia-inducible APCDD1L-AS1 promotes osimertinib resistance by stabilising DLST to drive tricarboxylic acid cycle in lung adenocarcinoma.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/40634956","citation_count":3,"is_preprint":false},{"pmid":"11825528","id":"PMC_11825528","title":"[Association between DLST gene polymorphism and Alzheimer's disease].","date":"2001","source":"Zhonghua yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/11825528","citation_count":3,"is_preprint":false},{"pmid":"37464884","id":"PMC_37464884","title":"Evolutionary trajectories of beta-lactamase NDM and DLST cluster in Pseudomonas aeruginosa: finding the putative ancestor.","date":"2023","source":"Pathogens and global health","url":"https://pubmed.ncbi.nlm.nih.gov/37464884","citation_count":2,"is_preprint":false},{"pmid":"41207382","id":"PMC_41207382","title":"Recommendations for Defining Chimeric Antigen Receptor T-Cell (CAR T) Dose-Limiting Toxicities (DLTs) for Future Early-Phase CAR T Therapy Studies.","date":"2025","source":"Transplantation and cellular therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41207382","citation_count":1,"is_preprint":false},{"pmid":"36634214","id":"PMC_36634214","title":"Candidate drugs associated with sensitivity of cancer cell lines with DLST amplification or high mRNA levels.","date":"2023","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/36634214","citation_count":1,"is_preprint":false},{"pmid":"38835385","id":"PMC_38835385","title":"Case report: A rare DLST mutation in patient with metastatic pheochromocytoma: clinical implications and management challenges.","date":"2024","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38835385","citation_count":1,"is_preprint":false},{"pmid":"19819302","id":"PMC_19819302","title":"A novel protein found in the I bands of myofibrils is produced by alternative splicing of the DLST gene.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19819302","citation_count":1,"is_preprint":false},{"pmid":"41616466","id":"PMC_41616466","title":"DLST mediates the malignant progression of osteosarcoma cells by regulating the p38 MAPK signaling pathway.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41616466","citation_count":0,"is_preprint":false},{"pmid":"41593675","id":"PMC_41593675","title":"Elevated miR-409-5p may promote the progression of osteoarthritis by targeting DLST as a potential biomarker function of miR-409-5p in osteoarthritis.","date":"2026","source":"Journal of orthopaedic surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/41593675","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.21.25324369","title":"Significance of the drug-induced lymphocyte stimulation test for various oral mesalamines in ulcerative colitis with mesalamine intolerance","date":"2025-03-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.21.25324369","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.02.25328445","title":"A first-in-human, Phase 1/2a, open-label study of SQ3370, a first-in-class doxorubicin-based click chemistry therapeutic, in patients with advanced solid tumors","date":"2025-06-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.02.25328445","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.11.612515","title":"Protein identification using cryo-EM and artificial intelligence guides improved sample purification","date":"2024-09-12","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.11.612515","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_2025.06.09.25329141","title":"Optimal dose and safety of intravenous favipiravir in hospitalised patients with SARS-CoV-2 infection: a Phase Ib, open-label, dose-escalating, randomised controlled study","date":"2025-06-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.09.25329141","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.07.24316829","title":"A Phase Ib/II multi-arm, dose finding and expansion study of a novel thymidylate synthase inhibitor with immune modulating properties, NUC-3373, in combination with pembrolizumab or docetaxel in patients with advanced solid tumors (NuTide:303)","date":"2024-11-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.07.24316829","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.25.24309146","title":"Sequential intravenous and intracerebroventricular GD2-CAR T-cell therapy for H3K27M-mutated diffuse midline gliomas","date":"2024-06-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.25.24309146","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21997,"output_tokens":3880,"usd":0.062095,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11732,"output_tokens":4369,"usd":0.083943,"stage2_stop_reason":"end_turn"},"total_usd":0.146038,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"KGD2 (yeast ortholog of DLST) encodes the dihydrolipoyl transsuccinylase (E2) component of the α-ketoglutarate dehydrogenase complex; chromosomal disruption of KGD2 abolished the ability of mitochondria to catalyze NAD+ reduction by α-ketoglutarate, establishing its essential catalytic role in the complex.\",\n      \"method\": \"Gene disruption (chromosomal KGD2 knockout), biochemical complementation assay, sequence analysis showing 42% identity to E. coli KE2\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — gene disruption with direct biochemical readout (loss of complex activity), replicated across multiple mutant strains, sequence-function correlation\",\n      \"pmids\": [\"2115121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"KGD2 transcription is activated by the HAP2 and HAP3 proteins via upstream sequence elements (244–484 nt upstream of the structural gene) containing HAP consensus cores, as shown by lacZ fusion assays in hap2 and hap3 mutant strains.\",\n      \"method\": \"lacZ promoter fusion assay, deletion analysis, Northern blot in wild-type vs. hap2/hap3 mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (lacZ fusions, deletion mapping, Northern blot) in the same study with genetic controls\",\n      \"pmids\": [\"2115121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The DLST gene is bifunctional: in addition to encoding the full-length mitochondrial E2 subunit, it produces a truncated protein (MIRTD) from an internal transcript starting in intron 7. MIRTD localizes to the mitochondrial intermembrane space and is required post-translationally for the stability/biogenesis of mitochondrial respiratory chain complexes I and IV.\",\n      \"method\": \"Novel mRNA cloning/sequencing, immunocytochemical localization, maxizyme (ribozyme)-mediated specific knockdown of MIRTD mRNA in SH-SY5Y cells, pulse-label experiment, measurement of respiratory complex subunit levels and activity\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — specific mRNA knockdown with multiple functional readouts (respiratory complex subunit levels, complex activity, pulse-label showing post-translational loss) in a single rigorous study\",\n      \"pmids\": [\"12805207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The DLST gene undergoes alternative splicing (deletion of exons 2 and 3, or exon 2, or exon 3) to produce a ~30 kDa protein that localizes to the I bands of myofibrils in rat skeletal muscle, distinct from the mitochondrial full-length DLST protein.\",\n      \"method\": \"Anti-DLST antibody immunocytochemical staining, protein purification and amino acid sequencing, cDNA isolation and sequencing of splicing variants\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein purification with sequence confirmation and immunolocalization, single lab, two orthogonal methods\",\n      \"pmids\": [\"19819302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of DLST function in zebrafish (schneckentempo mutant) causes severely reduced resting heart rate due to defective excitation generation in cardiac pacemaker cells; ATP levels are significantly diminished in mutant embryos, linking DLST-dependent TCA cycle activity to cardiac pacemaker energy supply.\",\n      \"method\": \"Positional cloning, gene knockdown (morpholino), external electrical pacing, ATP level measurement in mutant embryos\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — positional cloning combined with gene knockdown confirmation, functional electrophysiological rescue experiment, direct ATP measurement establishing mechanism\",\n      \"pmids\": [\"25697682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DLST (E2 transferase of α-KG dehydrogenase complex) is required for TCA cycle flux in T-ALL cells: RNAi knockdown causes accumulation of α-KG and decrease of succinyl-CoA, reduces cell viability, and induces apoptosis; addition of succinate (downstream TCA intermediate) rescues viability defects caused by DLST inactivation.\",\n      \"method\": \"RNAi knockdown, polar metabolomics profiling, cell viability assay, apoptosis assay, metabolite rescue experiment, zebrafish genetic model (heterozygous dlst inactivation delaying tumor onset)\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — metabolomics profiling of specific TCA substrates/products, genetic epistasis in zebrafish, metabolite rescue establishing pathway position, multiple orthogonal methods\",\n      \"pmids\": [\"26876595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Germline DLST variant p.Gly374Glu triggers accumulation of 2-hydroxyglutarate in tumors and in a heterologous cell-based functional assay, linking impaired DLST activity to oncometabolite production and pseudohypoxia-related epigenetic profiles in pheochromocytoma-paraganglioma.\",\n      \"method\": \"Targeted sequencing, 13C5-glutamate labeling assay, TCA-related metabolite determination, omics-based methylation/expression profiling, heterologous cell-based functional assay for DLST variants\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — 13C isotope tracing plus cell-based functional assay plus omics profiling, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"30929736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DLST loss in MYCN-amplified neuroblastoma cells suppresses NADH production and impairs oxidative phosphorylation (OXPHOS) without significantly altering TCA cycle metabolites other than α-KG accumulation, leading to growth arrest and apoptosis; monoallelic dlst loss in zebrafish impedes MYCN-driven tumor initiation.\",\n      \"method\": \"RNAi/shRNA depletion, NADH measurement, OXPHOS functional assays, metabolomics, zebrafish tumor model with dlst heterozygous loss, mouse xenograft model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (metabolomics, NADH/OXPHOS measurement, in vivo zebrafish and mouse models) from a single rigorous study\",\n      \"pmids\": [\"34233924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DLST depletion in DLST-dependent TNBC cells significantly alters TCA cycle metabolites and reactive oxygen species (ROS)-related pathways; DLST depletion increases ROS levels and N-acetyl-L-cysteine partially rescues cell growth, establishing a mechanistic link between DLST-mediated TCA activity and ROS homeostasis in these cancer cells.\",\n      \"method\": \"RNAi knockdown, metabolomics profiling, ROS level measurement, N-acetyl-L-cysteine rescue experiment, invasion assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (metabolomics, ROS assay, antioxidant rescue) in single lab\",\n      \"pmids\": [\"34785772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Germline DLST variants (p.Pro384Leu and p.Gly374Glu combined with somatic p.Thr383Ala) profoundly impact enzyme activity and result in DNA hypermethylation in pheochromocytoma-paraganglioma, as shown by functional assays on patient tumor material and engineered cell lines.\",\n      \"method\": \"In silico and functional enzyme activity assays, DNA methylation profiling, engineered cell lines expressing DLST variants\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional enzyme assay plus epigenetic readout in engineered cell lines, single lab\",\n      \"pmids\": [\"33180916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Grpel2 (a mitochondrial nucleotide exchange factor) physically interacts with DLST and positively mediates the import of DLST into mitochondria under high-glucose conditions; siRNA knockdown of DLST abolishes Grpel2-mediated protection of mitochondrial function and cardiomyocyte survival in diabetic cardiomyopathy.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), siRNA knockdown of DLST, mitochondrial ROS measurement, mitochondrial respiratory capacity assay, mitochondrial membrane potential assay, AAV9 overexpression in mouse model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP establishing interaction, functional rescue by DLST siRNA, multiple mitochondrial functional readouts, single lab\",\n      \"pmids\": [\"36927450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EPC1/2 regulate DLST expression via histone H3 acetylation at the DLST locus, acting cooperatively with transcription factors SRF and FOXR2; this EPC1/2–H3 acetylation–DLST axis is required for hematopoietic stem and progenitor cell (HSPC) emergence and proliferation.\",\n      \"method\": \"EPC1/2 depletion in zebrafish model, ChIP (H3 acetylation at DLST locus), HSPC quantification, K562 cell gene expression profiling\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating H3 acetylation at DLST locus, genetic depletion with HSPC phenotypic readout, single lab\",\n      \"pmids\": [\"38439957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The lncRNA APCDD1L-AS1, transcriptionally activated by HIF-1α under hypoxia, forms a complex with DLST and inhibits its ubiquitination and degradation, thereby stabilizing DLST protein and driving TCA cycle activity to promote osimertinib resistance in lung adenocarcinoma.\",\n      \"method\": \"Co-IP (APCDD1L-AS1–DLST complex), ubiquitination assay, lncRNA knockdown/overexpression, ChIP (HIF-1α binding to APCDD1L-AS1 promoter), in vitro and in vivo resistance models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing complex formation, ubiquitination assay demonstrating DLST stabilization mechanism, in vivo validation, single lab\",\n      \"pmids\": [\"40634956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DLST knockdown in osteosarcoma cells suppresses proliferation, migration, invasion, and promotes apoptosis; RNA-seq and pathway inhibitor experiments place DLST upstream of the p38 MAPK signaling pathway, with a p38 MAPK inhibitor reversing the malignant functional changes caused by DLST knockdown.\",\n      \"method\": \"siRNA knockdown, RNA-seq, pharmacological p38 MAPK inhibition (functional rescue), CCK-8, colony formation, scratch, transwell assays, animal tumor model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq pathway analysis combined with pharmacological rescue epistasis and in vivo validation, single lab\",\n      \"pmids\": [\"41616466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under glutamine deficiency, DLST (along with OGDH) relocalizes to the nucleus in muscle progenitor cells, where increased nuclear TCA enzyme presence correlates with elevated histone succinylation and reduced chromatin accessibility at the MyoD1 locus, impairing myogenesis.\",\n      \"method\": \"Confocal imaging of nuclear localization, succinyl-proteomics, single-cell nuclei ATAC sequencing, glutamine depletion experiments in human primary myoblasts (HSKM2) and C2C12 cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, localization data and epigenetic correlation without direct functional manipulation of DLST specifically\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DLST encodes the E2 dihydrolipoyl succinyltransferase core component of the α-ketoglutarate dehydrogenase complex (KGDHC), catalyzing the conversion of α-KG to succinyl-CoA in the TCA cycle to generate NADH for OXPHOS; it is imported into the mitochondrial matrix (assisted by Grpel2), regulated transcriptionally by histone H3 acetylation via EPC1/2 and by catabolite repression via HAP2/HAP3 (yeast), and its activity is required for NADH/ATP production, ROS homeostasis, and downstream MAPK signaling, while pathogenic variants impair enzyme activity leading to 2-hydroxyglutarate accumulation and DNA hypermethylation; the gene is also bifunctional, producing a truncated intermembrane-space protein (MIRTD) required for respiratory complex I and IV biogenesis, and alternative splicing generates a myofibrillar I-band isoform.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DLST encodes the dihydrolipoyl succinyltransferase (E2) core component of the α-ketoglutarate dehydrogenase complex, catalyzing conversion of α-ketoglutarate to succinyl-CoA in the TCA cycle; disruption of its yeast ortholog KGD2 abolishes mitochondrial NAD+ reduction by α-ketoglutarate, establishing its essential catalytic role [#0]. Through this activity DLST controls TCA flux and the downstream supply of NADH for oxidative phosphorylation: depletion arrests TCA cycle progression with α-KG accumulation and loss of succinyl-CoA, and the resulting energetic and metabolic defects drive apoptosis that is rescued by downstream intermediates such as succinate [#5, #7]. This DLST-dependent energy supply is physiologically required, exemplified by defective cardiac pacemaker excitation and reduced ATP in DLST-deficient zebrafish [#4]. In cancer contexts DLST is a metabolic dependency: it sustains NADH/OXPHOS and proliferation in MYCN-amplified neuroblastoma and T-ALL [#5, #7], regulates ROS homeostasis in triple-negative breast cancer [#8], and acts upstream of p38 MAPK signaling in osteosarcoma [#13]. Pathogenic germline DLST variants impair enzyme activity and cause accumulation of the oncometabolite 2-hydroxyglutarate with attendant DNA hypermethylation in pheochromocytoma-paraganglioma [#6, #9]. DLST levels are set both transcriptionally, through EPC1/2-mediated histone H3 acetylation acting with SRF and FOXR2 to drive hematopoietic progenitor emergence [#11], and post-translationally, through Grpel2-assisted mitochondrial import [#10] and lncRNA-mediated protection from ubiquitin-dependent degradation [#12]. The DLST locus is bifunctional, additionally producing a truncated intermembrane-space protein (MIRTD) required for biogenesis of respiratory complexes I and IV [#2], and alternative splicing yields a ~30 kDa myofibrillar I-band isoform [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established that DLST's ortholog is the catalytic E2 subunit of the α-ketoglutarate dehydrogenase complex and is indispensable for complex activity, defining its core biochemical function.\",\n      \"evidence\": \"Chromosomal KGD2 disruption with biochemical complementation assay and sequence analysis in yeast\",\n      \"pmids\": [\"2115121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Performed in yeast ortholog, not human DLST\", \"Structural basis of catalysis not resolved\", \"Regulation of complex assembly not addressed\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Showed the gene's transcription is under nutrient/catabolite control via HAP2/HAP3 activators, linking expression to respiratory metabolic demand.\",\n      \"evidence\": \"lacZ promoter fusions, deletion mapping, and Northern blot in hap2/hap3 mutant yeast\",\n      \"pmids\": [\"2115121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HAP-element regulation demonstrated only in yeast\", \"Human transcriptional control not addressed here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed the DLST locus is bifunctional, encoding a distinct intermembrane-space protein (MIRTD) needed for respiratory complex I and IV biogenesis beyond the matrix E2 enzyme.\",\n      \"evidence\": \"Novel transcript cloning, immunolocalization, and maxizyme-mediated MIRTD knockdown with respiratory complex readouts in SH-SY5Y cells\",\n      \"pmids\": [\"12805207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which MIRTD supports complex assembly unknown\", \"Interaction partners of MIRTD not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified a non-mitochondrial myofibrillar I-band isoform produced by alternative splicing, indicating tissue-specific functional diversification.\",\n      \"evidence\": \"Immunocytochemistry, protein purification with sequencing, and cDNA isolation of splice variants in rat skeletal muscle\",\n      \"pmids\": [\"19819302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of the I-band isoform unknown\", \"Demonstrated in rat only\", \"No catalytic or structural role established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected DLST-dependent TCA activity to organ physiology by showing its loss reduces ATP and impairs cardiac pacemaker excitation.\",\n      \"evidence\": \"Positional cloning, morpholino knockdown, electrical pacing rescue, and ATP measurement in zebrafish embryos\",\n      \"pmids\": [\"25697682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking ATP deficit to pacemaker excitation not fully resolved\", \"Tissue-specific dependency not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed DLST as a metabolic dependency in cancer, defining its pathway position via metabolite epistasis where downstream succinate rescues loss-of-function.\",\n      \"evidence\": \"RNAi, polar metabolomics, viability/apoptosis assays, metabolite rescue, and zebrafish genetic model in T-ALL\",\n      \"pmids\": [\"26876595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity of T-ALL dependence vs normal cells not fully defined\", \"Mechanism of apoptosis induction not specified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked impaired DLST enzyme function to oncometabolite (2-hydroxyglutarate) accumulation and pseudohypoxic epigenetic reprogramming in hereditary tumors.\",\n      \"evidence\": \"Targeted sequencing, 13C5-glutamate tracing, metabolite and methylation/expression profiling, and heterologous functional assay in pheochromocytoma-paraganglioma\",\n      \"pmids\": [\"30929736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic route from DLST deficiency to 2-HG production not mechanistically detailed\", \"Causality of methylation changes for tumorigenesis not proven\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Distinguished DLST's primary cancer-relevant output as NADH/OXPHOS support rather than broad TCA metabolite supply in MYCN-amplified neuroblastoma.\",\n      \"evidence\": \"shRNA depletion, NADH and OXPHOS assays, metabolomics, zebrafish and mouse xenograft tumor models\",\n      \"pmids\": [\"34233924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why only α-KG accumulates among TCA intermediates unexplained\", \"Generality across non-MYCN tumors not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established DLST control of ROS homeostasis as a determinant of cancer cell growth, with antioxidant rescue defining the link.\",\n      \"evidence\": \"RNAi, metabolomics, ROS measurement, and N-acetyl-L-cysteine rescue in triple-negative breast cancer cells\",\n      \"pmids\": [\"34785772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Source of elevated ROS upon DLST loss not pinpointed\", \"Partial rescue indicates additional mechanisms\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed specific germline DLST variants directly reduce enzyme activity and drive DNA hypermethylation in patient-derived and engineered systems.\",\n      \"evidence\": \"Functional enzyme activity assays, DNA methylation profiling, and engineered variant cell lines\",\n      \"pmids\": [\"33180916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanistic chain from activity loss to methylation not fully reconstituted\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified Grpel2 as a physical partner mediating glucose-dependent mitochondrial import of DLST, coupling import to cardiomyocyte protection.\",\n      \"evidence\": \"Reciprocal Co-IP, DLST siRNA, mitochondrial ROS/respiration/membrane potential assays, and AAV9 mouse model of diabetic cardiomyopathy\",\n      \"pmids\": [\"36927450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect Grpel2-DLST contact not structurally resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined an EPC1/2–histone H3 acetylation axis that transcriptionally activates DLST with SRF and FOXR2 to support hematopoietic stem and progenitor emergence.\",\n      \"evidence\": \"EPC1/2 depletion, ChIP for H3 acetylation at the DLST locus, HSPC quantification in zebrafish, and K562 expression profiling\",\n      \"pmids\": [\"38439957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of SRF/FOXR2 to DLST regulatory regions not fully mapped\", \"Whether DLST metabolic output mediates HSPC effect not proven\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed post-translational stabilization of DLST by a HIF-1α-induced lncRNA that blocks its ubiquitination, coupling hypoxia to DLST-driven therapy resistance.\",\n      \"evidence\": \"Co-IP of APCDD1L-AS1–DLST complex, ubiquitination assay, lncRNA knockdown/overexpression, HIF-1α ChIP, and in vivo resistance models in lung adenocarcinoma\",\n      \"pmids\": [\"40634956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase targeting DLST not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Positioned DLST upstream of p38 MAPK signaling as the route by which it promotes osteosarcoma malignancy.\",\n      \"evidence\": \"siRNA knockdown, RNA-seq, pharmacological p38 MAPK inhibition rescue, migration/invasion assays, and animal tumor model\",\n      \"pmids\": [\"41616466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular connection between DLST metabolism and p38 activation unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether DLST has a moonlighting nuclear, chromatin-modifying role via histone succinylation remains to be functionally established.\",\n      \"evidence\": \"Nuclear relocalization and succinyl-proteomics correlation under glutamine deficiency in myoblasts (preprint), without direct DLST manipulation\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"No direct functional manipulation of DLST tying nuclear localization to histone succinylation\", \"Causality for myogenesis impairment not demonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"complexes\": [\"α-ketoglutarate dehydrogenase complex (KGDHC)\"],\n    \"partners\": [\"GRPEL2\", \"EPC1\", \"EPC2\", \"OGDH\", \"APCDD1L-AS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}