Affinage

PDHA1

Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial · UniProt P08559

Length
390 aa
Mass
43.3 kDa
Annotated
2026-04-29
100 papers in source corpus 32 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDHA1 encodes the E1α catalytic subunit of the pyruvate dehydrogenase complex (PDHc), which irreversibly decarboxylates pyruvate to acetyl-CoA, linking glycolysis to the tricarboxylic acid cycle and serving as a central metabolic gatekeeper. PDHA1 activity is regulated by a multilayered post-translational code: inhibitory phosphorylation at Ser293 and Ser300 by pyruvate dehydrogenase kinases is counteracted by AMPK-mediated activating phosphorylation at Ser295 and Ser314 (PMID:33022274), while PLK1 phosphorylates Thr57 to target PDHA1 for mitophagy-dependent degradation (PMID:40957950); SIRT3-mediated deacetylation activates the enzyme (PMID:37479690), succinylation at Lys83 modulates its activity (PMID:40180922), and the E3 ligases UBE3A and RNF4 promote its proteasomal turnover (PMID:36920305, PMID:39521913). Pathogenic missense variants impair PDHc function through reduced thiamine pyrophosphate cofactor affinity and disrupted heterotetrameric assembly rather than solely through protein instability (PMID:33588022, PMID:29445841), and complete loss of Pdha1 in mice is embryonic lethal (PMID:11708858), while tissue-specific deletion causes organ-specific metabolic failure including cardiac ischemic vulnerability, hippocampal cognitive impairment, and compensatory glutamine dependence in cancer cells (PMID:26884059, PMID:34720870, PMID:27462778). Mutations in PDHA1 are a recognized cause of pyruvate dehydrogenase deficiency, a Mendelian disorder of mitochondrial energy metabolism (PMID:9818854, PMID:9671272).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1997 High

    The question of how the testis-specific PDHA2 isoform achieves tissue-restricted expression was answered by showing that CpG methylation at the ATF/CREB element within a minimal 187-bp promoter silences PDHA2 in non-testicular tissues, establishing epigenetic control of this locus.

    Evidence Transgenic mice with promoter-CAT reporters; in vitro methylation and mutagenesis of ATF/CREB site

    PMID:10766751 PMID:9001214

    Open questions at the time
    • Whether the same methylation mechanism governs PDHA1 (somatic isoform) expression is untested
    • Trans-acting factors beyond ATF/CREB that contribute to testis specificity were not identified
  2. 1998 High

    The molecular basis of disease-causing PDHA1 mutations was clarified: the R302C variant abolishes catalytic activity independent of major protein instability, establishing that residues near the phosphorylation loop are critical for catalysis, not merely regulation.

    Evidence Allele-specific cell lines from heterozygous female; reconstitution of R302C in E1α-null fibroblasts; PDH activity and turnover assays

    PMID:9671272 PMID:9818854

    Open questions at the time
    • Structural basis of how R302 participates in catalysis was modeled but not resolved crystallographically
    • Effects on TPP binding affinity were not measured for R302C at this time
  3. 1998 High

    A new mechanism of therapeutic action was discovered: chronic DCA stabilizes E1α protein by slowing its degradation rate ~twofold, independent of its known effect of promoting dephosphorylation, explaining how DCA can increase total PDH activity.

    Evidence Pulse-chase radiolabeling in normal and mutant fibroblast lines before and after DCA

    PMID:10449128 PMID:9818855

    Open questions at the time
    • The proteolytic pathway responsible for E1α turnover was not identified
    • Whether DCA-mediated stabilization operates in vivo in neurons or other tissues was not tested
  4. 2000 High

    The structural requirements for E1α2β2 heterotetramer assembly were defined: the C-terminal residues of E1α are essential for stability and/or assembly, with graded truncations producing proportional loss of protein and activity.

    Evidence Sequential C-terminal deletion mutants expressed in E1α-null fibroblasts with activity and immunoblot readouts

    PMID:10767328

    Open questions at the time
    • Whether C-terminal truncations affect E2/E3 binding or only E1α-E1β interaction was not resolved
    • No crystal structure of the truncated variants was obtained
  5. 2001 High

    PDHA1 was shown to be essential for early mammalian development: targeted deletion of exon 8 ablated PDHc activity in ES cells and caused embryonic lethality by E9.5, establishing that oxidative glucose metabolism via PDHc is non-redundant during postimplantation development.

    Evidence Cre/loxP conditional knockout in mouse ES cells and embryos; PDC activity assay and developmental phenotyping

    PMID:11708858

    Open questions at the time
    • Whether maternal PDHc provides partial rescue in early embryos was not determined
    • The specific metabolic deficiency (acetyl-CoA, NADH, or both) causing lethality was not dissected
  6. 2003 High

    A new disease mechanism was established: intronic and synonymous mutations in PDHA1 can create de novo SR protein binding sites that activate cryptic splice sites, causing pathogenic mRNA mis-splicing — expanding the mutational spectrum beyond coding changes.

    Evidence Minigene reconstitution in COS-7 cells; SC35 overexpression and siRNA knockdown in patient fibroblasts; RT-PCR

    PMID:12551913 PMID:15798212 PMID:18023225

    Open questions at the time
    • Prevalence of splicing mutations among undiagnosed PDH deficiency cases was not surveyed
    • Whether antisense oligonucleotides could correct the splicing defect was not tested
  7. 2012 High

    The assumption that PDH phosphorylation gates metabolic flux in all cell types was challenged: in pancreatic β-cells, complete suppression of PDK1/2/3 did not enhance pyruvate oxidation or insulin secretion, indicating that phosphorylation-independent mechanisms dominate metabolism-secretion coupling.

    Evidence Triple PDK1/2/3 siRNA knockdown in INS-1E cells; phospho-PDHA1 immunoblot; oxygen consumption and insulin secretion measurements

    PMID:22809973

    Open questions at the time
    • The alternative rate-limiting step in β-cell pyruvate oxidation was not identified
    • Whether PDH phosphatases compensate during PDK knockdown was not addressed
  8. 2015 High

    PI3K/Akt signaling was shown to maintain PDHA1 in its active (dephosphorylated) state, establishing a direct link between growth factor signaling and mitochondrial pyruvate oxidation.

    Evidence Pharmacologic PI3K/mTOR inhibition and inducible PTEN expression; phospho-Ser293 immunoblot; S293A mutagenesis; extracellular flux analysis

    PMID:25995437

    Open questions at the time
    • Whether PI3K acts by suppressing PDKs or activating PDPs was not fully resolved
    • Cell-type generalizability beyond the tested cancer lines was not established
  9. 2016 High

    Tissue-specific Pdha1 deletion revealed organ-specific consequences: cardiac knockout impaired ischemic glucose oxidation and blunted AMPK activation via disrupted Sestrin2–LKB1 interaction, while prostate cancer cell knockout triggered compensatory glutamine dependence through GLS1/GLUD1 upregulation.

    Evidence Cardiac-specific CreERT2 KO mice with LAD ligation and ex vivo perfusion; CRISPR KO in LNCaP cells with glutamine deprivation

    PMID:26884059 PMID:27462778

    Open questions at the time
    • How PDHc loss signals to upregulate glutaminolysis genes (transcriptional vs. metabolic feedback) was not resolved
    • Whether the Sestrin2-LKB1 disruption is a direct consequence of acetyl-CoA depletion was not tested
  10. 2018 High

    The structural basis of pathogenic variant effects was dissected at the protein level: different disease mutations cause distinct structural defects — disrupted heterodimer interfaces, TPP-sensitive conformations, or loss of E3 integration — and misfolded E1α can be trapped by Hsp60 chaperonin.

    Evidence Yeast expression system; electron microscopy; Hsp60 co-purification with ATP release; TPP concentration-dependent activity

    PMID:29445841

    Open questions at the time
    • Whether chaperone-assisted refolding is therapeutically exploitable was not tested
    • Structural analysis was performed in yeast, not with human PDHc
  11. 2020 High

    AMPK was identified as a direct mitochondrial matrix kinase of PDHA1, phosphorylating Ser295 (activating catalysis) and Ser314 (blocking PDK binding), providing a feed-forward mechanism linking energy stress to PDHc activation and TCA flux.

    Evidence In vitro kinase assays; phospho-site mutagenesis; mitochondrial matrix co-localization; mouse metastasis models

    PMID:33022274 PMID:33336150

    Open questions at the time
    • Whether AMPK-PDHA1 phosphorylation occurs in non-cancer tissues was not demonstrated
    • The phosphatase(s) that reverse Ser295/Ser314 phosphorylation were not identified
  12. 2021 High

    Pathogenic PDHA1 variants were unified by a shared biochemical defect: all tested variants exhibited 3–100× reduced TPP cofactor affinity, explaining loss of function even when protein stability is largely preserved.

    Evidence Purified recombinant PDC-E1 heterotetramers; enzymatic kinetics; TPP binding assays; molecular dynamics simulations

    PMID:33588022

    Open questions at the time
    • Whether high-dose thiamine therapy can overcome reduced TPP affinity for specific variants was not tested in this system
    • Only a subset of known clinical variants was characterized
  13. 2021 Medium

    Brain-specific consequences of PDHA1 loss were established: hippocampal Pdha1 deletion caused lactate accumulation and suppression of cAMP/PKA/CREB signaling, resulting in spatial memory impairment and neuronal ultrastructural damage.

    Evidence Hippocampus-specific Cre-lox Pdha1 KO mice; behavioral testing; electron microscopy; lactate and pathway measurements

    PMID:34720870

    Open questions at the time
    • Whether the cognitive deficit is reversible with metabolic intervention was not tested
    • The causal link between lactate accumulation and cAMP/PKA/CREB suppression was correlative
  14. 2022 Medium

    PDHA1 was linked to inflammasome activation: cardiac PDHA1 knockdown promoted NLRP3-mediated pyroptosis, and ISGylated Emerin was shown to bind PDHA1 and promote its inhibitory phosphorylation in lung cancer, connecting innate immunity and metabolic signaling to PDHc regulation.

    Evidence AAV-mediated PDHA1 KD in rat hearts with ischemia-reperfusion; EMD-PDHA1 Co-IP with phospho-PDHA1 readout in LUAD cells

    PMID:35506656 PMID:36071546

    Open questions at the time
    • Whether EMD-PDHA1 interaction occurs in non-cancer contexts was not tested
    • The mechanism by which PDHA1 loss activates NLRP3 (lactate, ROS, or acetyl-CoA depletion) was not resolved
  15. 2023 Medium

    The proteolytic regulation of PDHA1 was expanded by identification of two E3 ubiquitin ligases — UBE3A and RNF4 — that ubiquitinate PDHA1 and promote its proteasomal degradation, and SIRT3 was established as an activating deacetylase whose loss hyperacetylates PDHA1 and drives pathological lactate overproduction.

    Evidence Orthogonal ubiquitin transfer for UBE3A; Co-IP/ubiquitination assays and xenografts for RNF4; SIRT3 KD/OE with PDHA1 acetylation readouts in AKI models

    PMID:36920305 PMID:37479690 PMID:39521913

    Open questions at the time
    • The specific ubiquitination sites on PDHA1 were not mapped for UBE3A or RNF4
    • Whether SIRT3 and ubiquitin-mediated pathways converge on the same PDHA1 pool was not tested
    • UBE3A-PDHA1 relationship lacks reciprocal validation
  16. 2023 Medium

    Post-transcriptional regulation of PDHA1 was revealed: the m6A-modified circular RNA circRBM33 complexes with FMR1 to stabilize PDHA1 mRNA, enhancing PDHc-dependent mitochondrial metabolism in prostate cancer.

    Evidence RNA pulldown and RIP for circRBM33-FMR1; PDHA1 mRNA stability assays; metabolic measurements; in vivo tumor models

    PMID:37056926

    Open questions at the time
    • Whether circRBM33/FMR1 regulation of PDHA1 operates outside cancer contexts is unknown
    • The specific m6A sites on circRBM33 required for FMR1 binding were not fully mapped
  17. 2025 High

    Two new regulatory inputs to PDHA1 were identified: PLK1 phosphorylates Thr57, targeting PDHA1 for mitophagy and forcing a glycolytic-aspartate shuttle metabolic rewiring, while succinylation at Lys83 alters PDH activity and drives α-KG-mediated immune evasion in cholangiocarcinoma.

    Evidence SIRM metabolic flux with T57D phosphomimetic mice/MEFs; PLK1 inhibitor combination; PDHA1-K83 succinylation with macrophage OXGR1/MAPK/MHC-II assays

    PMID:40180922 PMID:40957950

    Open questions at the time
    • The mitophagy receptor(s) recognizing pT57-PDHA1 were not identified
    • Whether K83 succinylation is enzymatic or non-enzymatic was not determined
    • Physiological contexts in which PLK1-PDHA1 axis is relevant beyond cancer are unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full complement of E3 ligases and deubiquitinases controlling PDHA1 turnover, the structural basis of how activating versus inhibitory phosphorylation sites communicate within the E1α2β2 tetramer, and whether the diverse PTM inputs (phosphorylation, acetylation, succinylation, ubiquitination) are integrated combinatorially to generate a 'PTM code' that tunes PDHc flux in a tissue- and context-specific manner.
  • No integrated structural model of combinatorial PDHA1 PTM states exists
  • Deubiquitinases and desuccinylases for PDHA1 have not been identified
  • Tissue-specific quantitative flux measurements comparing PTM contributions are lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016491 oxidoreductase activity 4
Localization
GO:0005739 mitochondrion 5
Pathway
R-HSA-1430728 Metabolism 8 R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2
Partners
AMPK (PRKAA1/PRKAA2)EMDFMR1PDK4PLK1RNF4SIRT3UBE3A
Complex memberships
Pyruvate dehydrogenase complex (PDHc)

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 AMPK localizes to the mitochondrial matrix and directly phosphorylates PDHA1 (the catalytic alpha subunit of PDHc) at two residues: S295 (which activates enzymatic activity as an intrinsic catalytic site for pyruvate metabolism) and S314 (which abrogates the interaction between PDHA1 and PDHKs, leading to dephosphorylation of the inhibitory S293 site), thereby activating PDHc and driving TCA cycle flux to promote cancer metastasis. Co-localization in mitochondrial matrix, in vitro kinase assays, phospho-site mutagenesis, rescue experiments in mouse metastasis models Molecular cell High 33022274 33336150
2023 SIRT3-mediated deacetylation activates PDHA1; loss of SIRT3 causes hyperacetylation and inactivation of PDHA1, leading to lactate overproduction in renal tubular epithelial cells, which in turn drives Fis1 K20 lactylation, excessive mitochondrial fission, ATP depletion, mtROS overproduction, and mitochondrial apoptosis in sepsis-induced acute kidney injury. SIRT3 knockdown/overexpression in vitro and in vivo, sodium dichloroacetate (DCA) treatment, measurement of PDHA1 acetylation state, Fis1 lactylation assay, mitochondrial fission imaging Cell death & disease High 37479690
2015 PI3K/Akt/mTOR pathway activity suppresses PDHA1 Ser293 phosphorylation (keeping PDH active); pharmacologic or genetic inhibition of PI3K/Akt increases Ser293 phosphorylation on PDHA1, reducing oxygen consumption rate, an effect reversed by DCA or expression of phosphorylation-resistant PDHA1 S293A mutant. Pharmacologic inhibition (PI3K/mTOR inhibitors), inducible PTEN expression, DCA pre-treatment, phospho-site mutagenesis (S293A), extracellular flux analysis, Clark electrode oxygen measurement Molecular cancer therapeutics High 25995437
2001 Deletion of exon 8 of murine Pdha1 (encoding the E1α subunit) ablates PDH complex activity in embryonic stem cells; embryos carrying predominantly the null allele show global developmental delay by E9.5 and subsequent resorption, demonstrating an essential role for PDHA1-dependent oxidative glucose metabolism during early postimplantation development. Gene targeting (conditional knockout with Cre/loxP), in vitro PDC activity assay in ES cells, embryo phenotyping Molecular genetics and metabolism High 11708858
1998 Chronic dichloroacetate (DCA) treatment decreases the apparent first-order rate constant for degradation of the PDHA1 E1α subunit more than twofold in normal fibroblasts, selectively increasing total PDH activity by ~150%; this stabilization mechanism is distinct from DCA's known action of promoting the dephosphorylated (active) state. Pulse-chase radiolabeling to measure E1α subunit turnover before and after DCA treatment; PDH activity assay Neurology High 9818855
1999 Chronic DCA treatment increases steady-state PDHA1 E1α levels and slows E1α turnover ~twofold in cell lines carrying mutations that reduce E1α polypeptide stability (R378H, K387FS), increasing PDH activity by 25–31%; DCA treatment has no effect on PDH activity in the R302C mutant line, where the polypeptide has normal stability but reduced catalytic activity. PDH activity assays in defined mutant cell lines; pulse-chase measurement of E1α turnover before and after DCA; steady-state E1α immunoblot Neurology High 10449128
1998 The R302C missense mutation in PDHA1 causes severe PDH deficiency primarily through limitation of catalytic efficiency rather than polypeptide instability; the mutant E1α is only ~2–3-fold less stable than wild-type, yet residual activity is undetectable, suggesting that the R302 residue near the S300 regulatory phosphorylation site is critical for catalysis. Allele-specific cell lines from heterozygous female (expressing only mutant or only wild-type E1α); PDH activity, mRNA, protein expression, and turnover measurements Neurology High 9818854
1998 The R302C mutation in PDHA1 when expressed by transfection into E1α-null fibroblasts produces a protein devoid of enzymatic activity, demonstrating that this single amino acid change is sufficient to abolish PDH catalytic function. Transfection of mutant PDHA1 cDNA into E1α-deficient transformed fibroblasts followed by PDH activity assay Human mutation High 9671272
2000 Sequential deletion of C-terminal amino acids of PDHA1 E1α reveals that the C-terminus is required for stability and/or assembly of the E1α2β2 heterotetramer: deletion of 1, 2, 3, and 4 residues from the C-terminus yields PDHc activities of 100, 60, 36, and 14% of wild-type respectively, with proportional decreases in immunodetectable E1α protein. Expression of C-terminal deletion mutants by transfection into E1α-null fibroblasts; PDH activity assay; immunoblot Human molecular genetics High 10767328
2005 The SR protein SC35 binds to a novel site created by an intronic mutation downstream of exon 7 in PDHA1, activating a cryptic splice donor and causing intron retention; overexpression of SC35 enhanced cryptic splice site usage, and siRNA-mediated reduction of SC35 in patient fibroblasts nearly eliminated the aberrantly spliced E1α mRNA. SC35 overexpression and siRNA knockdown in patient fibroblasts; RT-PCR splicing analysis; in vitro splicing assays Molecular and cellular biology High 15798212
2003 An intronic G-to-A substitution 26 nt downstream of the exon 7 5'-splice site in PDHA1 generates a de novo SC35 consensus binding motif that activates a downstream cryptic 5'-splice site, causing retention of 45 nt of intron 7; COS-7 cell splicing assays confirmed the mutation causes the aberrant splicing phenotype. Genomic DNA sequencing, RT-PCR transcript analysis, minigene transfection in COS-7 cells, emetine treatment to stabilize aberrant transcripts The Journal of biological chemistry High 12551913
2007 Two silent substitutions in exon 5 of PDHA1 (c.483C>T and c.498C>T) disrupt a putative SRp55 exonic splicing enhancer near a weak intron 5 donor splice site, causing exon 5 skipping; minigene transfection experiments reproduced the splicing defect, and restoration of a perfect consensus 5' splice site by mutagenesis corrected it. Minigene transfection in COS-7 and HeLa cells; RT-PCR; in silico ESE prediction; site-directed mutagenesis of splice site Molecular genetics and metabolism High 18023225
2003 Pathogenicity of the D296E substitution in PDHA1 E1α was demonstrated by expression studies; the aspartate-to-glutamate change at position 296 is sufficient to cause PDH deficiency, and structural comparison with known E1 crystal structures suggests this residue is involved in maintaining active site geometry. Transfection/expression studies; structural modeling against known E1 crystal structures Human mutation Medium 14635113
2016 Cardiac-specific deletion of Pdha1 impairs glucose oxidation during ischemia/reperfusion in ex vivo working heart perfusion, increases infarct size and fibrosis, and blunts ischemic AMPK activation through disrupted Sestrin2-LKB1 interaction; DCA (PDH activator) rescues wild-type but not Pdha1-KO hearts. Inducible cardiac-specific CreERT2-PDH(flox/flox) KO mice; LAD ligation for myocardial infarction; ex vivo working heart perfusion with substrate metabolism measurement; DCA treatment; immunoblot for AMPK signaling Toxicological sciences High 26884059
2016 PDHA1 knockout in prostate cancer cells increases expression of glutaminase 1 (GLS1) and glutamate dehydrogenase 1 (GLUD1), rendering cells dependent on glutamine for survival; glutamine deprivation or pharmacologic glutaminolysis blockade induces apoptosis and elevated ROS in PDHA1 KO cells, demonstrating metabolic compensation. CRISPR/Cas9 PDHA1 KO in LNCaP cells; glutamine deprivation experiments; pharmacologic GLS1/GLUD1 inhibition; ROS and ATP measurement; cell viability and apoptosis assays Oncotarget High 27462778
2021 Hippocampus-specific Pdha1 knockout in mice causes lactate accumulation and inhibits the cAMP/PKA/CREB signaling pathway, resulting in spatial memory impairment and ultrastructural disorder of hippocampal neurons. Hippocampus-specific Cre-lox Pdha1 KO mice; behavioral tests (spatial memory); transmission electron microscopy; lactate measurement; RT-qPCR and Western blot for cAMP/PKA/CREB pathway components Frontiers in neuroscience Medium 34720870
2023 UBE3A/E6AP ubiquitinates PDHA1 and promotes its proteasomal degradation; UBE3A overexpression accelerates PDHA1 degradation and promotes glycolytic activity in HEK293 cells, identified by orthogonal ubiquitin transfer platform. Orthogonal ubiquitin transfer platform to identify substrates; UBE3A overexpression; degradation assays; glycolysis measurement Biochemistry Medium 36920305
2024 RNF4 ubiquitinates PDHA1 and promotes its degradation; RNF4 knockdown stabilizes PDHA1 protein, inhibits glycolytic flux, and suppresses tumor formation and metastasis in xenograft and metastasis models of colorectal cancer. Co-IP/pulldown to identify RNF4-PDHA1 interaction; RNF4 knockdown; ubiquitination assays; in vivo xenograft and metastasis models; metabolomic analysis NPJ precision oncology Medium 39521913
2025 PLK1 phosphorylates PDHA1 at threonine 57 (T57), driving its degradation via mitophagy and causing metabolic reprogramming from oxidative phosphorylation to glycolysis; cells mimicking T57 phosphorylation (T57D) rely more on the aspartate-malate shuttle than glucose-derived pyruvate to sustain TCA cycle, validated in MEFs and transgenic mice. Stable-isotope resolved metabolomics (SIRM); phosphomimetic PDHA1-T57D transgenic mice and MEFs; PLK1 inhibitor (Onvansertib) plus DCA combination; mitophagy assays Oncogene High 40957950
2022 ISGylation of Emerin (EMD) at lysine 37 inhibits its lysine 36 ubiquitination, stabilizing EMD; stabilized EMD binds PDHA1 via its β-catenin interaction domain, stimulates PDHA1 Ser293 and Ser300 phosphorylation (inhibitory), suppresses PDHA1 expression, and promotes glycolysis in lung adenocarcinoma. Co-IP demonstrating EMD-PDHA1 interaction; ISGylation site mapping; phospho-PDHA1 immunoblot; glycolysis measurements; correlation with clinical LUAD specimens Journal of cellular and molecular medicine Medium 36071546
2025 Succinylation of PDHA1 at lysine 83 alters PDH enzyme activity and modulates metabolic flux, leading to alpha-ketoglutaric acid (α-KG) accumulation in the cholangiocarcinoma tumor microenvironment; α-KG activates OXGR1 receptor on macrophages, triggering MAPK signaling and inhibiting MHC-II antigen presentation to promote immune escape. Omics analysis identifying PDHA1-K83 succinylation; PDH activity assays; metabolic flux measurement; macrophage OXGR1/MAPK/MHC-II functional assays; CPI-613 inhibitor treatment Nature communications Medium 40180922
2021 Structural and functional analysis of clinically relevant PDHA1 variants (including p.R253G) shows that all pathogenic variants exhibit ≈3–100× lower affinity for the thiamine pyrophosphate (TPP) cofactor compared to wild-type, with limited conformational stability changes but increased flexibility in the TPP binding region, as shown by MD simulations and in vitro enzymatic characterization of recombinant heterotetrameric PDC-E1. Expression and purification of recombinant PDC-E1 heterotetramers; enzymatic activity assays; TPP binding affinity measurements; molecular dynamics simulations Biochimie High 33588022
2018 In a yeast model, pathogenic E1α variants (corresponding to human A169V, M210V, R302C) cause distinct structural defects: A189V (heterodimer interface) leads to compact conformation and reduced E1 incorporation into PDC; M230V (tetramer/heterodimer interface) shows open conformation sensitive to low TPP; R322C (phosphorylation loop) results in PDC lacking E3 subunits and abolished activity; A189V variant E1α accumulates in Hsp60 chaperonin but can be released by ATP. Yeast expression system; PDC activity assays; structural analysis by electron microscopy; Hsp60 co-purification and ATP release experiments; TPP concentration dependence assays Cellular and molecular life sciences High 29445841
2006 PDHA2 (testis-specific E1α isoform) localizes extramitochondrially to the principal piece of hamster spermatozoa, co-localizing with AKAP4 in the fibrous sheath; PDHA enzymatic activity positively correlates with hyperactivation but not acrosome reaction, and PDHA2 undergoes capacitation-dependent tyrosine phosphorylation. Immunofluorescence and confocal microscopy; co-localization with AKAP4; enzymatic activity correlation with hyperactivation rates; tyrosine phosphorylation analysis during capacitation Biology of reproduction Medium 16855207
2012 In INS-1E pancreatic β-cells, glucose (but not other nutrient secretagogues) induces PDHA1 Ser phosphorylation via PDK1 and PDK3; however, preventing all PDH phosphorylation by triple PDK1/2/3 suppression neither enhances pyruvate oxidation nor insulin secretion, indicating that PDH phosphorylation per se does not control metabolism-secretion coupling. PDK1/2/3 siRNA knockdown; phospho-PDHA1 immunoblot; oxygen consumption measurement; insulin secretion assay Biochimica et biophysica acta High 22809973
2022 PDHA1 knockdown in kidney tubular cells decreases ATP production, NADH/NAD+ ratio, mitochondrial respiration, and induces impaired autophagic flux; co-culture of tubular cells with T1DM patient-derived CD4+ T cells (skewed toward Th1) impairs CPT1A, upregulates FASN, and causes kidney injury. PDHA1 siRNA knockdown in HK-2 cells; ATP/ROS/NADH:NAD+ measurement; mitochondrial respiration (Seahorse); autophagic flux assay; T cell co-culture experiments The Journal of clinical endocrinology and metabolism Medium 35731579
1997 Expression of the testis-specific Pdha-2 isoform is regulated by CpG methylation: only 187 bp of core promoter is sufficient for testis-specific CAT reporter expression in transgenic mice; in vitro methylation of the ATF/CREB element within the core promoter abolishes promoter activity, and mutation of this element reduces activity ~50%. Transgenic mice with promoter-CAT reporter deletions; in vitro methylation of promoter constructs; DNase I footprinting; site-directed mutagenesis of ATF/CREB element Molecular and cellular biology High 9001214
2000 Methylation-dependent repression of the Pdha-2 core promoter is mediated regionally through the ATF/CREB binding site at nucleotides -54 to -62; methylation of the single CpG within this element significantly disrupts promoter activity in vitro and completely abolishes activity in vivo. In vitro methylation of specific CpG dinucleotides followed by transfection; DNase I footprinting; in vivo transgenic reporter assays The Journal of biological chemistry High 10766751
2022 Insulin reduces NLRP3 inflammasome-mediated pyroptosis during myocardial ischemia-reperfusion injury by promoting PDHA1 dephosphorylation; AAV-mediated PDHA1 knockdown in cardiac cells promotes NLRP3 expression and blocks insulin's inhibitory effect on NLRP3-mediated pyroptosis. Ex vivo rat heart ischemia-reperfusion model; AAV-mediated PDHA1 knockdown; PDHc activity measurement; NLRP3/pyroptosis protein assays; immunohistochemistry Perfusion Medium 35506656
2023 m6A-modified circRBM33 interacts with FMR1 to form a binary complex that stabilizes PDHA1 mRNA, enhancing PDHA1-dependent mitochondrial metabolism (ATP production, acetyl-CoA, NADH/NAD+ ratio) and promoting prostate cancer progression; decreasing m6A levels rescues the tumor-promoting effect. RNA pulldown and RIP demonstrating circRBM33-FMR1 interaction; PDHA1 mRNA stability assay; m6A modification mapping; metabolic measurements (ATP, acetyl-CoA, NADH/NAD+); in vivo tumor models International journal of biological sciences Medium 37056926
2025 Sarcosine binds PDK4 and reduces PDHA1 phosphorylation, enhancing pyruvate dehydrogenase activity and increasing mitochondrial ROS production, thereby promoting ferroptosis; 15N-labeled metabolic flux analysis shows limited sarcosine-to-other-metabolite conversion in LUAD cells, and seahorse assays confirm metabolic shift from glycolysis to OXPHOS. Protein-ligand interaction (sarcosine-PDK4); 15N-labeled metabolic flux analysis; seahorse metabolic assay; phospho-PDHA1 immunoblot; ferroptosis markers (lipid-ROS, MDA, ferrous iron); PDO and xenograft models Experimental hematology & oncology Medium 40275333

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis. Molecular cell 159 33022274
2000 Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Human mutation 155 10679936
2023 PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation. Cell death & disease 141 37479690
2018 PGC1α promotes cholangiocarcinoma metastasis by upregulating PDHA1 and MPC1 expression to reverse the Warburg effect. Cell death & disease 71 29700317
2003 Antisense inhibition of mitochondrial pyruvate dehydrogenase E1alpha subunit in anther tapetum causes male sterility. The Plant journal : for cell and molecular biology 70 12662309
2001 Inactivation of the murine pyruvate dehydrogenase (Pdha1) gene and its effect on early embryonic development. Molecular genetics and metabolism 68 11708858
2018 miR‑21‑5p targets PDHA1 to regulate glycolysis and cancer progression in gastric cancer. Oncology reports 64 30226598
2015 The PI3K/Akt Pathway Regulates Oxygen Metabolism via Pyruvate Dehydrogenase (PDH)-E1α Phosphorylation. Molecular cancer therapeutics 60 25995437
2019 SIRT3 elicited an anti-Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis. Cancer medicine 57 30993888
2023 M6A-modified circRBM33 promotes prostate cancer progression via PDHA1-mediated mitochondrial respiration regulation and presents a potential target for ARSI therapy. International journal of biological sciences 55 37056926
2005 The SR protein SC35 is responsible for aberrant splicing of the E1alpha pyruvate dehydrogenase mRNA in a case of mental retardation with lactic acidosis. Molecular and cellular biology 55 15798212
1997 Regulation of Pdha-2 expression is mediated by proximal promoter sequences and CpG methylation. Molecular and cellular biology 55 9001214
2022 Comprehensive analyses of PDHA1 that serves as a predictive biomarker for immunotherapy response in cancer. Frontiers in pharmacology 47 36003495
2018 Overexpression of Pyruvate Dehydrogenase E1α Subunit Inhibits Warburg Effect and Induces Cell Apoptosis Through Mitochondria-Mediated Pathway in Hepatocellular Carcinoma. Oncology research 46 29444744
2011 Beneficial effect of pyruvate therapy on Leigh syndrome due to a novel mutation in PDH E1α gene. Brain & development 46 21454027
2021 Exosomal miR-21-5p derived from cisplatin-resistant SKOV3 ovarian cancer cells promotes glycolysis and inhibits chemosensitivity of its progenitor SKOV3 cells by targeting PDHA1. Cell biology international 45 34288231
2015 The oncoprotein HBXIP promotes glucose metabolism reprogramming via downregulating SCO2 and PDHA1 in breast cancer. Oncotarget 44 26309161
1988 Isolation and sequencing of a cDNA encoding the decarboxylase (E1)alpha precursor of bovine branched-chain alpha-keto acid dehydrogenase complex. Expression of E1 alpha mRNA and subunit in maple-syrup-urine-disease and 3T3-L1 cells. The Journal of biological chemistry 43 3379058
2019 PDHA1 Gene Knockout In Human Esophageal Squamous Cancer Cells Resulted In Greater Warburg Effect And Aggressive Features In Vitro And In Vivo. OncoTargets and therapy 39 31819487
2003 Splicing error in E1alpha pyruvate dehydrogenase mRNA caused by novel intronic mutation responsible for lactic acidosis and mental retardation. The Journal of biological chemistry 39 12551913
2004 Deficiency of pyruvate dehydrogenase caused by novel and known mutations in the E1alpha subunit. American journal of medical genetics. Part A 36 15384102
2016 Cardiac-Specific Deletion of the Pdha1 Gene Sensitizes Heart to Toxicological Actions of Ischemic Stress. Toxicological sciences : an official journal of the Society of Toxicology 35 26884059
2016 PDHA1 gene knockout in prostate cancer cells results in metabolic reprogramming towards greater glutamine dependence. Oncotarget 35 27462778
2006 Activity of pyruvate dehydrogenase A (PDHA) in hamster spermatozoa correlates positively with hyperactivation and is associated with sperm capacitation. Biology of reproduction 34 16855207
2000 Methylation-dependent silencing of the testis-specific Pdha-2 basal promoter occurs through selective targeting of an activating transcription factor/cAMP-responsive element-binding site. The Journal of biological chemistry 34 10766751
2004 IAR4, a gene required for auxin conjugate sensitivity in Arabidopsis, encodes a pyruvate dehydrogenase E1alpha homolog. Plant physiology 33 15173569
2004 Pyruvate dehydrogenase E1alpha subunit deficiency in a female patient: evidence of antenatal origin of brain damage and possible etiology of infantile spasms. Brain & development 32 14729417
2009 Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency. Clinical genetics 30 20002461
2007 Two silent substitutions in the PDHA1 gene cause exon 5 skipping by disruption of a putative exonic splicing enhancer. Molecular genetics and metabolism 30 18023225
2008 The involvement of the pyruvate dehydrogenase E1alpha subunit, in Streptococcus mutans acid tolerance. FEMS microbiology letters 29 19054088
1998 Stabilization of the pyruvate dehydrogenase E1alpha subunit by dichloroacetate. Neurology 29 9818855
1993 Temporal and tissue-specific interactions involving novel transcription factors and the proximal promoter of the mouse Pdha-2 gene. The Journal of biological chemistry 29 7693672
2014 Downregulation of a putative plastid PDC E1α subunit impairs photosynthetic activity and triacylglycerol accumulation in nitrogen-starved photoautotrophic Chlamydomonas reinhardtii. Journal of experimental botany 28 25210079
1994 Molecular basis of maple syrup urine disease: novel mutations at the E1 alpha locus that impair E1(alpha 2 beta 2) assembly or decrease steady-state E1 alpha mRNA levels of branched-chain alpha-keto acid dehydrogenase complex. American journal of human genetics 28 8037208
2001 Treatment of Raynaud's phenomenon with intravenous prostaglandin E1alpha-cyclodextrin improves endothelial cell injury in systemic sclerosis. The Journal of rheumatology 27 11327251
2021 Conditional Knockout of Pdha1 in Mouse Hippocampus Impairs Cognitive Function: The Possible Involvement of Lactate. Frontiers in neuroscience 26 34720870
2006 Somatic mosaicism in a male with an exon skipping mutation in PDHA1 of the pyruvate dehydrogenase complex results in a milder phenotype. Molecular genetics and metabolism 26 16412675
2008 Neonatal pyruvate dehydrogenase deficiency due to a R302H mutation in the PDHA1 gene: MRI findings. Pediatric radiology 25 18197404
2017 Alteration of mitochondrial protein PDHA1 in Lewy body disease and PARK14. Biochemical and biophysical research communications 24 28564592
1993 A eutherian X-linked gene, PDHA1, is autosomal in marsupials: a model for the evolution of a second, testis-specific variant in eutherian mammals. Genomics 24 8307573
2006 Females with PDHA1 gene mutations: a diagnostic challenge. Mitochondrion 23 16713755
2006 Acute flaccid paralysis as initial symptom in 4 patients with novel E1alpha mutations of the pyruvate dehydrogenase complex. Neuropediatrics 23 16967364
1986 Improved purification of the pyruvate dehydrogenase complex from Ascaris suum body wall muscle and characterization of PDHa kinase activity. Molecular and biochemical parasitology 23 3785292
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
1999 Dichloroacetate stabilizes the mutant E1alpha subunit in pyruvate dehydrogenase deficiency. Neurology 22 10449128
1998 Arginine 302 mutations in the pyruvate dehydrogenase E1alpha subunit gene: identification of further patients and in vitro demonstration of pathogenicity. Human mutation 22 9671272
2017 Distribution of the branched-chain α-ketoacid dehydrogenase complex E1α subunit and glutamate dehydrogenase in the human brain and their role in neuro-metabolism. Neurochemistry international 21 29104034
1999 Cerebral palsy and pyruvate dehydrogenase deficiency: identification of two new mutations in the E1alpha gene. European journal of pediatrics 20 10486093
1997 Transfection screening for primary defects in the pyruvate dehydrogenase E1alpha subunit gene. Human molecular genetics 20 9259285
2013 Mild phenotype in a male with pyruvate dehydrogenase complex deficiency associated with novel hemizygous in-frame duplication of the E1α subunit gene (PDHA1). Neuropediatrics 19 23572181
2008 Pyruvate dehydrogenase deficiency: identification of a novel mutation in the PDHA1 gene which responds to amino acid supplementation. European journal of pediatrics 19 18398624
2010 An animal model of PDH deficiency using AAV8-siRNA vector-mediated knockdown of pyruvate dehydrogenase E1α. Molecular genetics and metabolism 18 20685142
2023 Development and Evaluation of Recombinant B-Cell Multi-Epitopes of PDHA1 and GAPDH as Subunit Vaccines against Streptococcus iniae Infection in Flounder (Paralichthys olivaceus). Vaccines 17 36992208
2021 Daytime Dependence of the Activity of the Rat Brain Pyruvate Dehydrogenase Corresponds to the Mitochondrial Sirtuin 3 Level and Acetylation of Brain Proteins, All Regulated by Thiamine Administration Decreasing Phosphorylation of PDHA Ser293. International journal of molecular sciences 17 34360775
2017 Massive parallel sequencing identifies RAPSN and PDHA1 mutations causing fetal akinesia deformation sequence. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 17 28495245
2012 Pyruvate dehydrogenase E1α phosphorylation is induced by glucose but does not control metabolism-secretion coupling in INS-1E clonal β-cells. Biochimica et biophysica acta 17 22809973
1994 Differential expression of two testis-specific transcripts of the mouse Pdha-2 gene during spermatogenesis. DNA and cell biology 17 8024696
2013 Pyruvate dehydrogenase-e1α deficiency presenting as recurrent demyelination: an unusual presentation and a novel mutation. JIMD reports 16 23430811
2008 Somatic mosaicism for a PDHA1 mutation in a female with pyruvate dehydrogenase deficiency. Human genetics 15 18709504
2005 First characterization of a large deletion of the PDHA 1 gene. Molecular genetics and metabolism 15 16256390
1999 Characterization of the regulatory region of the human testis-specific form of the pyruvate dehydrogenase alpha-subunit (PDHA-2) gene. Biochimica et biophysica acta 15 10542321
2025 Cholangiocarcinoma PDHA1 succinylation suppresses macrophage antigen presentation via alpha-ketoglutaric acid accumulation. Nature communications 14 40180922
2012 Molecular genetic analysis of MSUD from India reveals mutations causing altered protein truncation affecting the C-termini of E1α and E1β. Journal of cellular biochemistry 14 22593002
2022 Insulin reduces pyroptosis-induced inflammation by PDHA1 dephosphorylation-mediated NLRP3 activation during myocardial ischemia-reperfusion injury. Perfusion 13 35506656
2020 AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis. Cell stress 13 33336150
2021 Structural and functional impact of clinically relevant E1α variants causing pyruvate dehydrogenase complex deficiency. Biochimie 12 33588022
2018 Identification of immunogenic proteins and evaluation of recombinant PDHA1 and GAPDH as potential vaccine candidates against Streptococcus iniae infection in flounder (Paralichthys olivaceus). PloS one 12 29847601
2002 Gene therapy for pyruvate dehydrogenase E1alpha deficiency using recombinant adeno-associated virus 2 (rAAV2) vectors. Molecular therapy : the journal of the American Society of Gene Therapy 12 12231176
2000 Sequential deletion of C-terminal amino acids of the E(1)alpha component of the pyruvate dehydrogenase (PDH) complex leads to reduced steady-state levels of functional E(1)alpha(2)beta(2) tetramers: implications for patients with PDH deficiency. Human molecular genetics 12 10767328
2023 Effects of UBE3A on Cell and Liver Metabolism through the Ubiquitination of PDHA1 and ACAT1. Biochemistry 11 36920305
2023 AP2α negatively regulates PDHA1 in cervical cancer cells to promote aggressive features and aerobic glycolysis in vitro and in vivo. Journal of gynecologic oncology 11 37055163
2022 T Cells Mediate Kidney Tubular Injury via Impaired PDHA1 and Autophagy in Type 1 Diabetes. The Journal of clinical endocrinology and metabolism 11 35731579
2009 Four novel PDHA1 mutations in pyruvate dehydrogenase deficiency. Journal of inherited metabolic disease 11 19517265
2006 A Korean female patient with thiamine-responsive pyruvate dehydrogenase complex deficiency due to a novel point mutation (Y161C)in the PDHA1 gene. Journal of Korean medical science 11 17043409
2019 Differential phenotypic expression of a novel PDHA1 mutation in a female monozygotic twin pair. Human genetics 10 31673819
2008 A putative exonic splicing enhancer in exon 7 of the PDHA1 gene affects splicing of adjacent exons. Human mutation 10 18273899
1998 Review: Pdha-2, past and present. The Journal of experimental zoology 10 9723179
2024 RNF4 mediated degradation of PDHA1 promotes colorectal cancer metabolism and metastasis. NPJ precision oncology 9 39521913
2022 ISGylation of EMD promotes its interaction with PDHA to inhibit aerobic oxidation in lung adenocarcinoma. Journal of cellular and molecular medicine 9 36071546
2021 Drug evaluation based on phosphomimetic PDHA1 reveals the complexity of activity-related cell death in A549 non-small cell lung cancer cells. BMB reports 9 34488935
2016 Pyruvate dehydrogenase-E1α deficiency presenting as recurrent acute proximal muscle weakness of upper and lower extremities in an 8-year-old boy. Neuromuscular disorders : NMD 9 27894792
2010 Somatic mosaicism for PDHA1 mutation in a male with pyruvate dehydrogenase complex deficiency. Molecular genetics and metabolism 9 20462777
2009 A cognitively normal PDH-deficient 18-year-old man carrying the R263G mutation in the PDHA1 gene. Journal of inherited metabolic disease 9 19639391
2007 Down-regulation of expression of rat pyruvate dehydrogenase E1alpha gene by self-complementary adeno-associated virus-mediated small interfering RNA delivery. Mitochondrion 9 17392036
2025 Exosomal miR-21-5p from glioma associated mesenchymal stem cells promotes the progression and glycolysis of glioblastoma via PDHA1. Scientific reports 8 39833311
2023 Artificial intelligence reveals dysregulation of osteosarcoma and cuproptosis-related biomarkers, PDHA1, CDKN2A and neutrophils. Scientific reports 8 36967449
2018 Folding and assembly defects of pyruvate dehydrogenase deficiency-related variants in the E1α subunit of the pyruvate dehydrogenase complex. Cellular and molecular life sciences : CMLS 8 29445841
2010 Thiamine ameliorates diabetes-induced inhibition of pyruvate dehydrogenase (PDH) in rat heart mitochondria: investigating the discrepancy between PDH activity and PDH E1alpha phosphorylation in cardiac fibroblasts exposed to high glucose. Journal of pharmacological sciences 8 20644337
2009 Maple syrup urine disease in Cypriot families: identification of three novel mutations and biochemical characterization of the p.Thr211Met mutation in the E1alpha subunit. Genetic testing and molecular biomarkers 8 19715473
2023 PDHA1 Alleviates Myocardial Ischemia-Reperfusion Injury by Improving Myocardial Insulin Resistance During Cardiopulmonary Bypass Surgery in Rats. Cardiovascular drugs and therapy 7 37610688
2022 SHP2 regulates adipose maintenance and adipocyte-pancreatic cancer cell crosstalk via PDHA1. Journal of cell communication and signaling 7 36074246
2021 codY and pdhA Expression Is Induced in Staphylococcus epidermidis Biofilm and Planktonic Populations With Higher Proportions of Viable but Non-Culturable Cells. Frontiers in cellular and infection microbiology 7 34869073
2015 Development of a loop-mediated isothermal amplification targeting a gene within the pyruvate dehydrogenase complex, the pdhA gene, for rapid detection of Mycoplasma gallisepticum. Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc 7 26038479
2003 A pathogenic glutamate-to-aspartate substitution (D296E) in the pyruvate dehydrogenase E1 subunit gene PDHA1. Human mutation 7 14635113
2025 Sarcosine sensitizes lung adenocarcinoma to chemotherapy by dual activation of ferroptosis via PDK4/PDHA1 signaling and NMDAR-mediated iron export. Experimental hematology & oncology 6 40275333
2019 Epigallocatechin-3-gallate downregulates PDHA1 interfering the metabolic pathways in human herpesvirus 8 harboring primary effusion lymphoma cells. Toxicology in vitro : an international journal published in association with BIBRA 6 31857147
1998 An integrated genetic and man-mouse comparative map of the DXHXS674-Pdha1 region of the mouse X chromosome. Genomics 6 9503026
1998 Mechanisms of expression of pyruvate dehydrogenase deficiency caused by an E1alpha subunit mutation. Neurology 6 9818854
1994 Mouse testis Pdha-2 promoter upstream sequences confer tissue-and temporal-specific activity in transgenic mice. Reproduction, fertility, and development 6 7569039
2025 PLK1-mediated PDHA1 phosphorylation drives metabolic reprogramming in lung cancer. Oncogene 5 40957950