Affinage

DLST

Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial · UniProt P36957

Length
453 aa
Mass
48.8 kDa
Annotated
2026-04-28
30 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DLST encodes the E2 dihydrolipoyl succinyltransferase subunit of the mitochondrial α-ketoglutarate dehydrogenase complex (KGDHC), catalyzing the conversion of α-ketoglutarate to succinyl-CoA in the TCA cycle and generating NADH for oxidative phosphorylation (PMID:2115121, PMID:26876595, PMID:34233924). The DLST locus is bifunctional: in addition to the full-length E2 enzyme, an alternative transcript from intron 7 encodes MIRTD, a truncated protein localizing to the mitochondrial intermembrane space that is required for biogenesis of respiratory chain complexes I and IV (PMID:12805207), and further splice variants produce a ~30 kDa isoform that localizes to myofibril I bands in skeletal muscle (PMID:19819302). DLST protein stability is regulated post-translationally by lncRNAs (MEG3, APCDD1L-AS1) that bind DLST and prevent its ubiquitin-dependent proteasomal degradation (PMID:37506369, PMID:40634956), and its mitochondrial import is facilitated by the co-chaperone Grpel2 (PMID:36927450). Germline loss-of-function DLST mutations cause accumulation of the oncometabolite 2-hydroxyglutarate and DNA hypermethylation, establishing DLST as a susceptibility gene for pheochromocytoma and paraganglioma (PMID:30929736, PMID:33180916).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1990 High

    Establishing the core catalytic identity of DLST: disruption of the yeast ortholog KGD2 abolished α-ketoglutarate-dependent mitochondrial NAD⁺ reduction, proving DLST encodes the E2 transsuccinylase essential for KGDHC activity.

    Evidence Gene disruption, complementation, and enzymatic activity assay in yeast

    PMID:2115121

    Open questions at the time
    • Mammalian DLST function not yet directly demonstrated
    • Structural basis of transsuccinylation not resolved
    • Regulatory mechanisms unknown
  2. 2003 High

    Revealing that the DLST locus is bifunctional: a truncated protein (MIRTD), transcribed from intron 7, localizes to the mitochondrial intermembrane space and is required for respiratory chain complexes I and IV biogenesis, showing DLST contributes to OXPHOS beyond its TCA cycle role.

    Evidence Specific mRNA knockdown by maxizymes, pulse-label experiments, subcellular fractionation, and complex activity assays in human cells

    PMID:12805207

    Open questions at the time
    • Mechanism by which MIRTD promotes complex I/IV assembly unknown
    • Whether MIRTD acts as a chaperone, assembly factor, or import mediator not determined
  3. 2009 Medium

    Demonstrating that DLST splice variants have non-mitochondrial functions: a ~30 kDa isoform lacking exons 2–3 localizes to myofibril I bands in skeletal muscle, suggesting a structural or regulatory role at the sarcomere.

    Evidence Immunocytochemistry, protein purification, amino acid sequencing, and cDNA cloning from rat skeletal muscle

    PMID:19819302

    Open questions at the time
    • Function of the myofibrillar isoform not determined
    • Single study in rat tissue without genetic confirmation
    • Whether this isoform exists in human muscle unknown
  4. 2015 High

    Linking DLST to cardiac physiology: positional cloning of a zebrafish bradycardia mutant mapped to DLST, showing that DLST loss reduces ATP production and impairs pacemaker cell excitation, establishing an in vivo physiological role for KGDHC-derived ATP in heart rate regulation.

    Evidence Forward genetic screen, positional cloning, gene knockdown, ATP measurement, and electrical pacing in zebrafish

    PMID:25697682

    Open questions at the time
    • Whether cardiac phenotype is specific to DLST or general KGDHC deficiency not distinguished
    • Mammalian cardiac phenotype of DLST loss not established
  5. 2016 High

    Placing DLST as a metabolic vulnerability in cancer: knockdown in MYC-driven T-ALL cells accumulated α-KG and depleted succinyl-CoA, and succinate rescue confirmed the TCA cycle bottleneck, demonstrating DLST is a required metabolic node for certain oncogene-driven tumors.

    Evidence RNAi knockdown, polar metabolomics, succinate rescue, and zebrafish genetic model in human T-ALL cells

    PMID:26876595

    Open questions at the time
    • Whether DLST dependency generalizes beyond MYC-driven contexts not clear
    • Therapeutic targeting strategy not developed
  6. 2019 High

    Establishing DLST as a pheochromocytoma/paraganglioma susceptibility gene: the germline p.Gly374Glu variant abolished DLST enzymatic function and caused accumulation of the oncometabolite 2-hydroxyglutarate with pseudohypoxic DNA methylation profiles, mechanistically linking DLST loss-of-function to tumorigenesis.

    Evidence ¹³C₅-glutamate isotope tracing, cell-based enzyme assay, TCA metabolite profiling, DNA methylation analysis, and LOH analysis in patient tumors

    PMID:30929736

    Open questions at the time
    • Penetrance and genotype-phenotype correlations for different DLST variants not established
    • Source of 2-HG production (enzymatic versus non-enzymatic) not fully resolved
  7. 2021 High

    Dissecting the downstream consequence of DLST loss in tumors: DLST depletion in MYCN-amplified neuroblastoma primarily impaired NADH production and OXPHOS rather than anaplerosis, while in TNBC cells DLST loss elevated ROS as a key mediator of growth inhibition, clarifying tissue-specific metabolic consequences.

    Evidence shRNA depletion, metabolomics, NADH/OXPHOS measurements, ROS assays, NAC rescue, and in vivo xenograft models across neuroblastoma and TNBC cell lines

    PMID:34233924 PMID:34785772

    Open questions at the time
    • Whether NADH versus ROS mechanisms are context-dependent or coexistent not resolved
    • Specific ROS species and downstream signaling pathways not fully characterized
  8. 2021 Medium

    Extending the disease genetics: additional DLST variants (p.Pro384Leu, compound heterozygous p.Gly374Glu/p.Thr383Ala) were shown to impair enzymatic activity and produce DNA hypermethylation, confirming that multiple loss-of-function alleles converge on the same pathogenic mechanism in pheochromocytoma/paraganglioma.

    Evidence Functional enzyme activity assays and DNA methylation profiling of patient-derived tumor samples

    PMID:33180916

    Open questions at the time
    • Structural basis for why these specific residues are critical not determined
    • Animal models recapitulating DLST-driven PPGL not available
  9. 2023 Medium

    Identifying regulators of DLST protein stability and mitochondrial import: Grpel2 physically interacts with DLST and promotes its mitochondrial import under high-glucose conditions, while lncRNA MEG3 binds DLST protein and prevents its degradation, revealing post-translational control layers for DLST abundance.

    Evidence Co-IP, mitochondrial import assays, RNA pulldown, RIP-qPCR, knockdown/overexpression rescue in cardiomyocytes and porcine satellite cells

    PMID:36927450 PMID:37506369

    Open questions at the time
    • Ubiquitin ligase(s) targeting DLST not identified
    • Whether Grpel2-DLST interaction is direct or complex-mediated not resolved
    • Grpel2 interaction validated by co-IP only without reciprocal pull-down
  10. 2024 Medium

    Connecting DLST transcriptional control to chromatin regulation: EPC1/2 promote DLST expression via histone H3 acetylation in cooperation with SRF and FOXR2, linking epigenetic regulators to mitochondrial metabolism in hematopoietic stem and progenitor cell proliferation.

    Evidence Zebrafish EPC1/2 depletion, ChIP-based H3 acetylation analysis, gene expression profiling in K562 cells

    PMID:38439957

    Open questions at the time
    • Whether EPC1/2 directly binds the DLST promoter not confirmed
    • DLST's specific role in HSPC biology is inferred rather than directly tested
  11. 2025 Medium

    Expanding DLST's post-translational regulation: lncRNA APCDD1L-AS1, transcriptionally activated by HIF-1α under hypoxia, binds DLST protein and prevents its ubiquitination and proteasomal degradation, thereby sustaining TCA cycle flux to drive osimertinib resistance in lung adenocarcinoma.

    Evidence Co-IP/complex formation, ubiquitination assay, knockdown/overexpression, luciferase reporter, in vivo drug resistance models

    PMID:40634956

    Open questions at the time
    • Identity of the E3 ubiquitin ligase for DLST still unknown
    • Whether APCDD1L-AS1 blocks a specific ubiquitin site on DLST not determined
    • Single study without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the E3 ubiquitin ligase(s) targeting DLST for degradation, the molecular mechanism by which MIRTD promotes respiratory chain complex assembly, and whether nuclear translocation of DLST under nutrient stress represents a physiologically important epigenetic regulatory mechanism.
  • E3 ligase for DLST not identified
  • MIRTD mechanism of action in complex I/IV assembly unknown
  • Nuclear DLST and histone succinylation link requires peer-reviewed confirmation
  • Structural basis of DLST catalysis and disease variants not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3
Localization
GO:0005739 mitochondrion 5 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-1643685 Disease 2
Partners
APCDD1L-AS1DLDGRPEL2MEG3OGDH
Complex memberships
α-ketoglutarate dehydrogenase complex (KGDHC)

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 KGD2 (yeast ortholog of DLST) encodes the dihydrolipoyl transsuccinylase (KE2) component of the α-ketoglutarate dehydrogenase complex; disruption abolishes mitochondrial NAD+ reduction by α-ketoglutarate, establishing its essential catalytic role in the complex Gene disruption, complementation, enzymatic activity assay, sequence analysis showing 42% identity to E. coli KE2 Molecular and cellular biology High 2115121
2003 The DLST gene is bifunctional: a novel truncated protein (MIRTD), transcribed from intron 7 of DLST and localizing to the mitochondrial intermembrane space, is required for biogenesis of respiratory chain complexes I and IV via a post-translational mechanism Novel mRNA identification, subcellular fractionation/localization, maxizyme-mediated specific mRNA knockdown, pulse-label experiment, Western blot quantification of complex subunits and activity assays The EMBO journal High 12805207
2009 The DLST gene produces a ~30 kDa alternative splice variant (lacking exons 2 and 3, or exon 2, or exon 3) that localizes to the I bands of myofibrils in rat skeletal muscle, representing a protein with a distinct non-mitochondrial function Immunocytochemical staining with anti-DLST antibody, protein purification, amino acid sequencing, cDNA isolation and sequencing Biochimica et biophysica acta Medium 19819302
2015 Loss of DLST function in zebrafish (positional cloning of schneckentempo mutant) reduces ATP production and causes bradycardia due to defective cardiac pacemaker cell excitation, establishing DLST's role in heart rate regulation via mitochondrial ATP supply Forward genetic screen, positional cloning, gene knockdown, electrical pacing, ATP level measurement Basic research in cardiology High 25697682
2016 DLST, as the E2 transferase of the α-ketoglutarate dehydrogenase complex (KGDHC), converts α-KG to succinyl-CoA in the TCA cycle; its knockdown in human T-ALL cells accumulates α-KG and depletes succinyl-CoA, and succinate supplementation rescues viability, placing DLST as a required TCA cycle node for MYC-driven leukemogenesis RNAi knockdown, polar metabolomics profiling, succinate rescue experiment, zebrafish genetic model (heterozygous inactivation) Leukemia High 26876595
2019 Germline DLST variant p.Gly374Glu causes loss of enzymatic function, triggers accumulation of 2-hydroxyglutarate in tumors and in heterologous cell-based assays, and is associated with pseudohypoxia (EPAS1-like methylation/expression profiles), linking DLST dysfunction to oncometabolite production and pheochromocytoma/paraganglioma susceptibility Targeted sequencing, 13C5-glutamate labeling assay, TCA metabolite determination, methylation profiling, heterologous cell-based functional assay, loss of heterozygosity analysis American journal of human genetics High 30929736
2021 DLST depletion in MYCN-amplified neuroblastoma cells suppresses NADH production and impairs OXPHOS without substantially altering TCA cycle metabolites other than α-KG accumulation, demonstrating that DLST's primary contribution to tumor growth is through NADH/OXPHOS support rather than anaplerosis per se RNAi/shRNA depletion, metabolomics, NADH measurement, OXPHOS functional assays, zebrafish and mouse xenograft models Cancer research High 34233924
2021 DLST depletion in DLST-dependent TNBC cells increases reactive oxygen species (ROS) and disrupts TCA cycle and ROS-related pathways; N-acetyl-L-cysteine partially rescues growth, implicating ROS as a downstream mediator of DLST loss-of-function RNAi knockdown, metabolomics profiling, ROS measurement, N-acetyl-L-cysteine rescue experiment, in vivo tumor models Communications biology High 34785772
2021 DLST variants (p.Pro384Leu and compound heterozygous p.Gly374Glu/p.Thr383Ala) profoundly impact DLST enzyme activity and result in DNA hypermethylation in pheochromocytoma/paraganglioma tumor cells In silico predictions, functional enzyme activity assays, DNA methylation analysis, compound heterozygous variant characterization The Journal of clinical endocrinology and metabolism Medium 33180916
2023 Grpel2 physically interacts with DLST (shown by co-IP) and positively mediates the import of DLST into mitochondria under high-glucose conditions; DLST knockdown abrogates the protective effects of Grpel2 overexpression on mitochondrial function and cardiomyocyte survival in diabetic cardiomyopathy Co-immunoprecipitation, siRNA knockdown, mitochondrial import assay (overexpression rescue), ROS/membrane potential/respiratory capacity measurements Journal of translational medicine Medium 36927450
2023 lncRNA MEG3 binds DLST protein (shown by RNA pulldown and RIP-qPCR) and stabilizes DLST protein post-translationally (MEG3 overexpression increases DLST protein without changing mRNA); DLST promotes porcine satellite cell (skeletal muscle) differentiation, and the MYOD→MEG3→DLST axis regulates myogenesis RNA pulldown, RIP-qPCR, knockdown/overexpression experiments, rescue assays, ChIP and luciferase reporter for MYOD binding to MEG3 promoter, in vivo knockdown Epigenetics Medium 37506369
2024 EPC1/2 regulate DLST expression through histone H3 acetylation, cooperating with transcription factors SRF and FOXR2, and DLST links EPC1/2 function to mitochondrial metabolism in hematopoietic stem and progenitor cell (HSPC) proliferation Zebrafish genetic depletion of EPC1/2, ChIP-based H3 acetylation analysis, gene expression profiling in K562 cells iScience Medium 38439957
2025 lncRNA APCDD1L-AS1 forms a complex with DLST protein and prevents its ubiquitination and proteasomal degradation, thereby stabilizing DLST and driving TCA cycle activity to promote osimertinib resistance in lung adenocarcinoma; HIF-1α transcriptionally activates APCDD1L-AS1 under hypoxia Co-IP/complex formation assay, ubiquitination assay, knockdown/overexpression, luciferase reporter for HIF-1α binding, in vitro and in vivo drug resistance models Journal of experimental & clinical cancer research Medium 40634956
2026 DLST knockdown in osteosarcoma cells inhibits proliferation, migration, invasion, and promotes apoptosis; RNA-seq and pharmacological inhibition revealed DLST regulates the p38 MAPK signaling pathway, with p38 MAPK inhibition reversing malignant phenotypes caused by DLST knockdown RNAi knockdown, RNA-seq, p38 MAPK inhibitor rescue, CCK-8/colony/transwell/flow cytometry assays, in vivo xenograft Biochemical and biophysical research communications Medium 41616466
2025 Under glutamine deficiency, DLST (along with OGDH) translocates to the nucleus in muscle progenitor cells, leading to elevated histone succinylation and restricted chromatin accessibility at the MyoD1 locus, impairing myogenesis Confocal imaging of nuclear localization, succinyl-proteomics, single-cell nuclei ATAC-seq, cell proliferation/cycle assays bioRxiv (preprint)preprint Low bio_10.1101_2025.05.30.657066

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 Structure and regulation of KGD2, the structural gene for yeast dihydrolipoyl transsuccinylase. Molecular and cellular biology 55 2115121
2021 Metabolic Enzyme DLST Promotes Tumor Aggression and Reveals a Vulnerability to OXPHOS Inhibition in High-Risk Neuroblastoma. Cancer research 51 34233924
2016 The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis. Leukemia 50 26876595
2021 DLST-dependence dictates metabolic heterogeneity in TCA-cycle usage among triple-negative breast cancer. Communications biology 49 34785772
2019 Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas. American journal of human genetics 48 30929736
1999 Modulation by DLST of the genetic risk of Alzheimer's disease in a very elderly population. Annals of neurology 35 9894876
2015 Loss of dihydrolipoyl succinyltransferase (DLST) leads to reduced resting heart rate in the zebrafish. Basic research in cardiology 26 25697682
2003 Truncated product of the bifunctional DLST gene involved in biogenesis of the respiratory chain. The EMBO journal 24 12805207
1999 A DLST genotype associated with reduced risk for Alzheimer's disease. Neurology 24 10227647
1999 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. Hepatology (Baltimore, Md.) 22 10385636
2009 Usefulness of double locus sequence typing (DLST) for regional and international epidemiological surveillance of methicilin-resistant Staphylococcus aureus. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 17 19832717
2003 Promiscuous T cells selected by Escherichia coli: OGDC-E2 in primary biliary cirrhosis. Journal of autoimmunity 17 12753811
2001 No association between DLST gene and Alzheimer's disease or Wernicke-Korsakoff syndrome. Neurobiology of aging 11 11445257
1995 Mutation analysis of the chromosome 14q24.3 dihydrolipoyl succinyltransferase (DLST) gene in patients with early-onset Alzheimer disease. Neuroscience letters 11 8584231
2021 Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma. The Journal of clinical endocrinology and metabolism 9 33180916
2023 Grpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through DLST-mediated mitochondrial dysfunction: a proof-of-concept study. Journal of translational medicine 7 36927450
2023 MYOD induced lnc-MEG3 promotes porcine satellite cell differentiation via interacting with DLST. Epigenetics 7 37506369
2019 Rno-miR-425-5p targets the DLST and SLC16A1 genes to reduce liver damage caused by excessive energy mobilization under cold stress. Journal of animal physiology and animal nutrition 7 31087708
2006 [DLST as a method for detecting TS-1-induced allergy]. Gan to kagaku ryoho. Cancer & chemotherapy 7 16531715
2024 EPC1/2 regulate hematopoietic stem and progenitor cell proliferation by modulating H3 acetylation and DLST. iScience 6 38439957
2018 Association of OGG1 and DLST promoter methylation with Alzheimer's disease in Xinjiang population. Experimental and therapeutic medicine 4 30214536
2025 Hypoxia-inducible APCDD1L-AS1 promotes osimertinib resistance by stabilising DLST to drive tricarboxylic acid cycle in lung adenocarcinoma. Journal of experimental & clinical cancer research : CR 3 40634956
2001 [Association between DLST gene polymorphism and Alzheimer's disease]. Zhonghua yi xue za zhi 3 11825528
2023 Evolutionary trajectories of beta-lactamase NDM and DLST cluster in Pseudomonas aeruginosa: finding the putative ancestor. Pathogens and global health 2 37464884
2025 Recommendations for Defining Chimeric Antigen Receptor T-Cell (CAR T) Dose-Limiting Toxicities (DLTs) for Future Early-Phase CAR T Therapy Studies. Transplantation and cellular therapy 1 41207382
2024 Case report: A rare DLST mutation in patient with metastatic pheochromocytoma: clinical implications and management challenges. Frontiers in oncology 1 38835385
2023 Candidate drugs associated with sensitivity of cancer cell lines with DLST amplification or high mRNA levels. Oncotarget 1 36634214
2009 A novel protein found in the I bands of myofibrils is produced by alternative splicing of the DLST gene. Biochimica et biophysica acta 1 19819302
2026 Elevated miR-409-5p may promote the progression of osteoarthritis by targeting DLST as a potential biomarker function of miR-409-5p in osteoarthritis. Journal of orthopaedic surgery and research 0 41593675
2026 DLST mediates the malignant progression of osteosarcoma cells by regulating the p38 MAPK signaling pathway. Biochemical and biophysical research communications 0 41616466