Affinage

PDHA1

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

Length
390 aa
Mass
43.3 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDHA1 encodes the catalytic E1α subunit of the pyruvate dehydrogenase complex (PDHc), which directs oxidative glucose metabolism; its loss ablates PDHc activity and is essential for early post-implantation development and tissue homeostasis in heart, brain, and other organs (PMID:11708858, PMID:26884059, PMID:34720870, PMID:20685142). E1α assembles into a heterotetrameric (α₂β₂) holoenzyme whose stability and catalysis depend on intact protein architecture: progressive C-terminal deletions destabilize the tetramer and abolish activity, and clinically relevant missense variants act either by lowering thiamine pyrophosphate (TPP) cofactor affinity, by perturbing heterodimer/tetramer interfaces, or by impairing the active site directly (e.g., R302C, D296E) rather than by destabilizing the protein (PMID:10767328, PMID:33588022, PMID:29445841, PMID:14635113, PMID:9818854). PDHc flux is gated by reversible phosphorylation of E1α: activating phosphorylation by AMPK at S295 and S314 (the latter blocking inhibitory PDK phosphorylation at S293) drives TCA-cycle flux, while PI3K/Akt/mTOR and PDK-mediated phosphorylation at S293/S300 suppress respiration and favor glycolysis (PMID:33022274, PMID:33336150, PMID:25995437, PMID:36071546, PMID:22809973). Additional layers of control include PLK1 phosphorylation at T57 triggering mitophagic degradation, ubiquitin-mediated turnover by UBE3A and RNF4, SIRT3-reversible acetylation, K83 succinylation, and direct arsenic binding that competes with TPP — modifications that collectively shift cells between oxidative and glycolytic metabolism and, in cancer, promote glycolysis, metastasis, and immune escape (PMID:40957950, PMID:36920305, PMID:39521913, PMID:37479690, PMID:40180922, PMID:40961697). Loss-of-function defects in PDHA1, including missense, deletion, and splicing-disrupting mutations that abolish E1α activity or expression, cause human pyruvate dehydrogenase deficiency (PMID:9671272, PMID:9259285, PMID:15798212, PMID:18273899). Reduced PDHc activity drives lactate accumulation that feeds downstream signaling such as Fis1 and histone lactylation (PMID:37479690, PMID:34720870, PMID:40961697); pharmacologically, dichloroacetate (DCA) both promotes dephosphorylation and stabilizes E1α, raising activity selectively for stability-affected mutant alleles (PMID:9818855, PMID:10449128).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Established how the testis-specific Pdha promoter is restricted in expression, defining epigenetic control of the Pdha gene family.

    Evidence transgenic mice with Pdha-2 promoter deletions, in vitro CpG methylation, DNase I footprinting, ATF/CREB site mutagenesis

    PMID:9001214

    Open questions at the time
    • Addresses the testis isoform promoter, not somatic PDHA1 regulation
    • No link to enzyme assembly or activity
  2. 1998 Medium

    Resolved the mechanism by which a recurrent pathogenic mutation causes enzyme deficiency, distinguishing loss of catalysis from protein instability.

    Evidence X-inactivation-isolated isogenic fibroblasts and transfection complementation in E1α-null cells with PDH activity and turnover assays (R302C)

    PMID:9259285 PMID:9671272 PMID:9818854

    Open questions at the time
    • Single residue characterized in detail
    • No structural model of the perturbed active site beyond proximity to S300
  3. 1999 Medium

    Defined a second, phosphorylation-independent mechanism for DCA action by showing it stabilizes E1α, explaining mutation-selective therapeutic response.

    Evidence pulse-chase turnover and PDH activity assays in normal and mutant (R378H, K387fs, R302C) PDH-deficient fibroblasts after chronic DCA

    PMID:10449128 PMID:9818855

    Open questions at the time
    • Molecular basis of DCA-mediated stabilization not defined
    • Effect restricted to stability-affecting mutations
  4. 2000 Medium

    Mapped a structural determinant of holoenzyme assembly, showing the E1α C-terminus is required for stable α₂β₂ heterotetramer formation.

    Evidence sequential C-terminal deletion mutants expressed in E1α-null fibroblasts with PDH activity assays and immunoblotting

    PMID:10767328

    Open questions at the time
    • No atomic structure of the C-terminal assembly contacts
    • Somatic vs testis isoform equivalence shown only functionally
  5. 2001 High

    Established that PDHA1-mediated oxidative glucose metabolism is essential for early mammalian development.

    Evidence conditional Pdha1 exon 8 deletion in ES cells and embryos with PDC activity assays and developmental phenotyping

    PMID:11708858

    Open questions at the time
    • Does not dissect tissue-specific requirements
    • Mechanism of developmental arrest not defined at the cellular level
  6. 2007 High

    Showed that many PDHA1 'point' mutations act by disrupting exonic and intronic splicing regulatory elements rather than coding sequence, recruiting SR proteins (SC35, SRp40, SRp55) to cause aberrant splicing.

    Evidence minigene transfection assays, SC35 overexpression and siRNA knockdown in patient fibroblasts, silent/synonymous mutation comparisons

    PMID:12551913 PMID:15798212 PMID:18023225 PMID:18273899

    Open questions at the time
    • Each ESE/ISE characterized in heterologous or single-patient systems
    • Quantitative contribution to disease severity not established
  7. 2015 High

    Placed PI3K/Akt/mTOR signaling upstream of E1α S293 phosphorylation, linking growth-factor signaling to PDHc-controlled respiration.

    Evidence PI3K/mTOR inhibition, PTEN induction, S293 phospho-immunoblotting, S→A phospho-resistant mutant, DCA, and oxygen consumption measurements

    PMID:25995437

    Open questions at the time
    • Intermediary kinase/PDK steps between Akt and S293 not fully resolved
    • Performed largely in cancer cell models
  8. 2018 High

    Connected distinct pathogenic E1α variants to specific structural defects — interface destabilization, TPP sensitivity, and loss of E3 incorporation — and implicated Hsp60 chaperonin handling.

    Evidence yeast expression of A189V/M230V/R322C variants, native gels, PDC activity, TPP titration, Hsp60 co-IP, ATP-release experiments

    PMID:29445841

    Open questions at the time
    • Heterologous yeast system
    • Chaperonin handling not validated in human cells
  9. 2020 High

    Identified AMPK as a direct activating kinase of E1α (S295, S314) that relieves PDK inhibition and drives TCA flux to support cancer metastasis under metabolic stress.

    Evidence in vitro kinase assays, S295A/S314A mutagenesis, mitochondrial co-localization, metabolic flux and mouse metastasis models

    PMID:33022274 PMID:33336150

    Open questions at the time
    • Stoichiometry/relative contribution of S295 vs S314 in vivo not fully quantified
    • How AMPK accesses the mitochondrial matrix not detailed
  10. 2023 High

    Defined SIRT3-reversible acetylation as a switch controlling E1α activity, with downstream lactate-driven Fis1 lactylation linking PDHA1 inactivation to mitochondrial fission and tissue injury.

    Evidence SIRT3 KO/OE in vitro and in vivo, PDHA1 acetylation assays, Fis1 K20 lactylation assays, mitochondrial morphology imaging, DCA rescue

    PMID:37479690

    Open questions at the time
    • Specific PDHA1 acetylation site(s) not pinpointed
    • Acetyltransferase counteracting SIRT3 not identified
  11. 2024 Medium

    Expanded the ubiquitin-mediated control of E1α abundance, identifying UBE3A and RNF4 as E3 ligases whose action lowers PDHA1 and promotes glycolysis and metastasis.

    Evidence orthogonal ubiquitin transfer platform (UBE3A), Co-IP/ubiquitination assays and RNF4 knockdown with xenograft/metastasis models

    PMID:36920305 PMID:39521913

    Open questions at the time
    • Ubiquitination sites on PDHA1 not mapped
    • Each ligase shown by a single lab
  12. 2025 High

    Revealed PLK1-driven T57 phosphorylation as a trigger for mitophagic PDHA1 degradation that reprograms metabolism toward glycolysis and aspartate-malate shuttle reliance.

    Evidence PLK1 kinase assay, phosphomimetic T57D knock-in mice and MEFs, SIRM metabolic flux, mitophagy assays

    PMID:40957950

    Open questions at the time
    • Mitophagy receptor coupling T57 phosphorylation to degradation not identified
    • Physiological context of PLK1-PDHA1 signaling beyond models unclear
  13. 2025 High

    Demonstrated K83 succinylation of PDHA1 as a metabolic-immune coupling event, where altered flux generates α-KG that activates macrophage OXGR1 to drive immune escape in cholangiocarcinoma.

    Evidence succinylation omics, K83 site identification, metabolic flux, macrophage OXGR1/MAPK and MHC-II assays, in vivo tumor models with CPI-613

    PMID:40180922

    Open questions at the time
    • Succinyltransferase/desuccinylase regulating K83 not defined
    • Generalizability beyond cholangiocarcinoma unknown
  14. 2025 Medium

    Established direct arsenic binding to PDHA1 that competes with TPP, lowering activity and driving lactate-dependent histone lactylation and inflammasome activation.

    Evidence molecular docking, SEC binding assays, fluorescent arsenic co-localization, H3K18 lactylation MS/CUT&Tag, TPP competition screening, in vivo arsenic exposure

    PMID:40961697

    Open questions at the time
    • Arsenic binding residue(s) not biochemically mapped
    • Computational TPP competition not fully validated structurally

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many overlapping post-translational layers (phosphorylation by AMPK/PLK1/PDK, ubiquitination, acetylation, succinylation) are integrated and prioritized to set PDHc flux in a given cell state remains unresolved.
  • No unified model of cross-talk among modification sites
  • Site occupancy under physiological conditions not quantified
  • Tissue-specific dominance of each regulatory input unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 5 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1430728 Metabolism 4
Partners
AMPKEMDPDHBPDK4PLK1RNF4SIRT3UBE3A
Complex memberships
E1 (α₂β₂) heterotetramerpyruvate dehydrogenase complex (PDHc)

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 AMPK directly phosphorylates PDHA1 (the catalytic alpha subunit of PDHc) at two residues: S295 (an activating phosphorylation that serves as an intrinsic catalytic site required for pyruvate metabolism) and S314 (which alleviates inhibitory phosphorylation by PDHKs, including blocking PDHK-mediated phosphorylation at S293). AMPK co-localizes with PDHA1 in the mitochondrial matrix. These phosphorylation events activate PDHc enzymatic activity and drive TCA cycle flux to support cancer metastasis under metabolic stress. Co-localization (mitochondrial matrix), in vitro kinase assay, phospho-specific mutagenesis (S295A, S314A), mouse metastasis models, metabolic flux assays Molecular cell High 33022274 33336150
2023 SIRT3 deacetylates PDHA1; loss of SIRT3 leads to hyperacetylation and inactivation of PDHA1, resulting in increased lactate production in renal tubular epithelial cells. The downstream lactate mediates K20 lactylation of mitochondrial fission protein Fis1, promoting excessive mitochondrial fission, ATP depletion, mtROS overproduction, and apoptosis. SIRT3 overexpression or PDHA1 activation with DCA decreases lactate levels and Fis1 lactylation, alleviating sepsis-induced acute kidney injury. SIRT3 knockout/overexpression in vitro and in vivo, acetylation assays on PDHA1, lactylation assays on Fis1 K20, mitochondrial morphology imaging, metabolic measurements Cell death & disease High 37479690
2025 PDHA1 is succinylated at lysine 83 in cholangiocarcinoma; this succinylation alters PDH enzyme activity and modulates metabolic flux, leading to alpha-ketoglutaric acid (α-KG) accumulation in the tumor microenvironment. Accumulated α-KG activates the OXGR1 receptor on macrophages, triggering MAPK signaling and inhibiting MHC-II antigen presentation, thereby promoting immune escape. Inhibiting PDHA1 succinylation with CPI-613 enhances chemotherapy efficacy. Omics succinylation analysis, site-specific K83 identification, metabolic flux analysis, macrophage OXGR1 receptor activation assays, MAPK signaling assays, MHC-II antigen presentation assays, in vivo tumor models Nature communications High 40180922
2015 Inhibition of the PI3K/Akt/mTOR pathway increases phosphorylation of PDHA1 E1α at Ser293, thereby inhibiting PDHc activity and decreasing oxygen consumption rate. Expressing a phosphorylation-resistant (serine-to-alanine) PDHA1 mutant or using DCA to inhibit PDK-mediated phosphorylation reversed the decrease in oxygen consumption caused by PI3K/mTOR inhibition, placing PI3K/Akt upstream of PDHA1 phosphorylation in the regulation of mitochondrial respiration. Pharmacological PI3K/mTOR inhibition, inducible PTEN expression, phospho-specific Ser293 immunoblotting, PDHA1 phospho-mutant (S→A) overexpression, oxygen consumption rate measurements (Clark electrode and extracellular flux analyzer), DCA treatment Molecular cancer therapeutics High 25995437
2025 PLK1 (polo-like kinase 1) phosphorylates PDHA1 at threonine 57 (T57), driving PDHA1 protein 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 on glucose-derived pyruvate for TCA cycle sustenance. This was confirmed in mouse embryonic fibroblasts and transgenic mice conditionally expressing PDHA1-T57D. Stable-isotope resolved metabolomics (SIRM), phosphomimetic PDHA1-T57D knock-in mice and MEFs, PLK1 kinase assay, mitophagy assays, metabolic flux analysis Oncogene High 40957950
2023 UBE3A (E3 ubiquitin ligase) ubiquitinates PDHA1, accelerating its proteasomal degradation. UBE3A overexpression reduces PDHA1 protein levels and promotes glycolytic activity in HEK293 cells. This was identified using an orthogonal ubiquitin transfer platform. Orthogonal ubiquitin transfer platform to identify substrates, overexpression of UBE3A in HEK293 cells, degradation assays, glycolysis measurements Biochemistry Medium 36920305
2024 RNF4 is an E3 ubiquitin ligase that mediates ubiquitination and degradation of PDHA1 in colorectal cancer cells, thereby promoting glycolytic metabolism and metastasis. RNF4 knockdown stabilizes PDHA1 protein levels and inhibits tumor formation and metastasis in vivo. Proteomic and TCGA/CPTAC database analysis, Co-IP/ubiquitination assays identifying RNF4 as PDHA1 E3 ligase, in vitro PDHA1 overexpression/RNF4 KD experiments, xenograft and metastasis mouse models, metabolomic analysis NPJ precision oncology Medium 39521913
2022 EMD (Emerin), whose stability is enhanced by ISGylation at K37 (which inhibits K36 ubiquitination), binds PDHA1 via its β-catenin interaction domain, stimulates phosphorylation of PDHA1 at S293 and S300, and inhibits PDHA1 expression, thereby inhibiting aerobic oxidation and facilitating glycolysis. EMD ISGylation is required for the EMD-PDHA1 interaction. Co-IP with domain mapping (β-catenin interaction domain of EMD), phospho-specific immunoblotting for PDHA1 S293/S300, ISGylation site mutagenesis (K37), cell metabolic assays, clinical tissue correlation Journal of cellular and molecular medicine Medium 36071546
2012 PDK1, PDK2, and PDK3 expressed in pancreatic β-cells mediate phosphorylation of PDHA1 E1α in response to glucose stimulation; however, suppression of PDK1 and PDK3 (preventing E1α phosphorylation) did not enhance pyruvate oxidation or insulin secretion, indicating that PDH E1α phosphorylation control by PDKs does not itself alter metabolism-secretion coupling in INS-1E cells. PDK1/2/3 knockdown by siRNA, phospho-specific E1α immunoblotting, pyruvate oxidation assays, insulin secretion assays in INS-1E cells and rat islets Biochimica et biophysica acta Medium 22809973
1998 Chronic dichloroacetate (DCA) treatment increases the stability of PDHA1 E1α subunit, reducing its rate of degradation more than twofold and increasing total PDH activity by ~150%, via a mechanism distinct from its known effect of promoting dephosphorylation (activation) of the complex. Pulse-chase metabolic labeling to measure E1α turnover rate in normal fibroblasts before and after DCA treatment, PDH activity assays Neurology Medium 10449128 9818855
1999 Chronic DCA treatment stabilizes mutant PDHA1 E1α polypeptides that have reduced stability (e.g., R378H, K387fs mutations), increasing PDH activity by ~25-31% in these cell lines. In contrast, DCA did not increase PDH activity in a cell line with the R302C mutation where the mutant polypeptide has normal stability but reduced catalytic activity, demonstrating that DCA's mechanism of action is selective for stability-affecting mutations. Chronic DCA treatment of PDH-deficient fibroblast cell lines with defined mutations, PDH activity assays, E1α steady-state level measurement, subunit turnover assays Neurology Medium 10449128
1998 The R302C missense mutation in PDHA1 results in loss of catalytic activity as the primary mechanism of enzyme deficiency, with only a modest 2-3 fold reduction in steady-state mutant E1α protein level. The primary mechanism is thus limitation of catalytic efficiency, likely because R302 is adjacent to S300, an important regulatory phosphorylation site, and conformational changes near this residue impair catalysis. X-inactivation-based isolation of fibroblast cell lines expressing exclusively mutant or wild-type E1α alleles, PDH activity assays, mRNA and protein quantification, polypeptide turnover measurements Neurology Medium 9818854
1998 The R302C mutation in PDHA1 demonstrated to abolish enzymatic activity when transfected into human fibroblast cell lines lacking endogenous E1α mRNA and protein, establishing pathogenicity. A transfection-based complementation system was developed to screen for E1α gene defects by restoring enzyme activity in E1α-null transformed fibroblasts. Transfection of normal and mutant PDHA1 cDNA into E1α-null transformed fibroblast cell lines, PDH enzymatic activity assays Human mutation Medium 9259285 9671272
2000 Sequential C-terminal deletions of PDHA1 E1α progressively reduce PDH complex activity and immunodetectable E1α protein levels, demonstrating that the C-terminus is required for stable assembly of the E1α2β2 heterotetramer; deletion of 1, 2, 3, or 4 C-terminal amino acids results in 100%, 60%, 36%, and 14% activity respectively. The somatic and testis-specific E1α isoforms are biochemically equivalent when expressed in PDH-deficient cells. Expression of C-terminal deletion mutants in E1α-null fibroblast cell lines, PDH activity assays, immunoblotting Human molecular genetics Medium 10767328
2021 Structural and functional analysis of clinically relevant PDHA1 E1α variants (in reconstituted heterotetrameric αα'ββ' PDC-E1) showed that all variants have ≈3-100× lower affinity for the thiamine pyrophosphate (TPP) cofactor compared to wild-type, and reduced residual enzymatic activity, despite limited impact on overall conformational stability. The p.R253G variant shows increased propensity for aggregation. Molecular dynamics simulations show increased flexibility in the TPP binding region for all variants. Recombinant heterotetrameric PDC-E1 reconstitution, TPP binding affinity assays, enzymatic activity measurements, molecular dynamics simulations, biophysical characterization Biochimie High 33588022
2018 Using a yeast model expressing pathogenic E1α variants (A189V at the heterodimer interface, M230V at the tetramer/heterodimer interface, R322C in the phosphorylation loop), each substitution causes distinct structural changes: A189V leads to a more compact conformation with underrepresentation of E1 in PDC; M230V leads to a more open conformation with sensitivity to low thiamine pyrophosphate; R322C results in PDC lacking E3 subunits and abolished activity. The A189V variant accumulates in Hsp60 chaperonin but can be released by ATP supplementation. Yeast expression system for PDC-E1α variants, native gel electrophoresis, PDC activity assays, thiamine pyrophosphate titration, Hsp60 co-immunoprecipitation, ATP-release experiments Cellular and molecular life sciences : CMLS High 29445841
2001 Homozygous deletion of exon 8 of murine Pdha1 ablates PDC activity in embryonic stem cells, and embryos carrying predominantly the Pdha1(Deltaex8) allele are globally delayed in development by 9.5 days postcoitus with subsequent resorption, establishing an essential role for PDHA1-mediated oxidative glucose metabolism in early post-implantation development. Gene targeting (loxP/Cre conditional knockout), in vitro PDC activity assays in ES cells, embryo developmental analysis Molecular genetics and metabolism High 11708858
2016 Cardiac-specific deletion of Pdha1 impairs glucose oxidation in hearts during ischemia/reperfusion, increases myocardial infarct size, macrophage infiltration, hypertrophy, and fibrosis. Mechanistically, cardiac PDHA1 deficiency impairs ischemic AMPK activation through the Sestrin2-LKB1 interaction, sensitizing hearts to ischemic stress. DCA (PDH activator) increased glucose oxidation and reduced infarct size in wild-type but not in PDH E1α-deficient hearts. Inducible cardiac-specific Cre-loxP knockout (CreERT2-PDHflox/flox), ex vivo working heart perfusion with metabolic measurements, myocardial infarction model, immunoblotting for AMPK/Sestrin2/LKB1, histological analysis, DCA rescue experiment Toxicological sciences High 26884059
2021 Conditional knockout of Pdha1 in mouse hippocampus impairs spatial memory and causes ultrastructural disorder of hippocampal neurons. PDHA1 deficiency causes lactate accumulation and abnormal lactate transport, and inhibits the cAMP/PKA/CREB signaling pathway, suggesting lactate accumulation as a mediator of cognitive impairment. Hippocampus-specific Cre-loxP conditional KO, behavioral tests (spatial memory), transmission electron microscopy, lactate level measurements, RT-qPCR and western blotting for cAMP/PKA/CREB pathway components Frontiers in neuroscience Medium 34720870
2006 PDHA2 (the testis-specific isoform of PDHA, forming the PDHA tetramer with PDHB) undergoes capacitation-dependent tyrosine phosphorylation in hamster spermatozoa. PDHA (the active αα'ββ' tetramer) localizes extramitochondrially in the principal piece of the flagellum, co-localizing with AKAP4 in the fibrous sheath. PDHA enzymatic activity correlates positively with sperm hyperactivation but not the acrosome reaction. Immunofluorescence and confocal microscopy for subcellular localization, AKAP4 co-localization, tyrosine phosphorylation immunoblotting, enzymatic activity assay correlated with capacitation events Biology of reproduction Medium 16855207
2025 Arsenic binds directly to PDHA1, reducing PDH enzymatic activity. This was demonstrated by molecular docking, size exclusion chromatography assays, and fluorescence-labeled arsenic co-localization assays. The reduction in PDH activity promotes conversion of pyruvate to lactate, which induces H3K18 lactylation and activates the CD36-NLRP3 inflammasome axis. Thiamine pyrophosphate (TPP) competitively inhibits arsenic binding to PDHA1. Molecular docking, size exclusion chromatography (SEC) binding assays, fluorescence-labeled arsenic co-localization, mass spectrometry for H3K18 lactylation, CUT&Tag, high-throughput virtual screening for TPP competition, in vivo mouse arsenic exposure model Journal of hazardous materials Medium 40961697
2022 In a rat myocardial ischemia-reperfusion injury model, insulin reduces NLRP3-mediated pyroptosis via a mechanism dependent on PDHA1 dephosphorylation. Knockdown of PDHA1 promoted NLRP3 expression and blocked the inhibitory effect of insulin on NLRP3-mediated pyroptosis, placing PDHA1 downstream of insulin signaling and upstream of NLRP3 activation. Recombinant adenoviral vector PDHA1 knockdown, ex vivo heart ischemia/reperfusion model, PDHc activity measurements, NLRP3 and pyroptosis marker immunoblotting, myocardial infarction size measurement Perfusion Medium 35506656
2003 The SR protein SC35 is responsible for aberrant splicing of PDHA1 mRNA caused by an intronic mutation that creates a de novo SC35 binding site. Ectopic overexpression of SC35 enhanced use of the cryptic splice site, and siRNA-mediated reduction of SC35 in patient fibroblasts caused near-complete disappearance of the aberrantly spliced PDHA1 mRNA, demonstrating a mechanistic role for SC35 in this splicing defect. SC35 overexpression in cells, siRNA knockdown of SC35 in patient fibroblasts, RT-PCR analysis of splicing products Molecular and cellular biology High 15798212
2003 An intronic point mutation at intron 7 position 26 (G→A) in PDHA1 creates a de novo SC35 consensus binding motif, switching splicing from the normal 5' splice site to a cryptic downstream site and inserting 45 nt of intron 7. This was confirmed by splicing assays in COS-7 cells with the mutant construct. Genomic DNA sequencing, COS-7 cell transfection with mutant minigene, RT-PCR analysis of splicing products The Journal of biological chemistry Medium 12551913
2007 A nonsense mutation (Y243X) and a silent mutation at the same position in exon 7 of PDHA1 both disrupt a strong SRp40 consensus binding site, causing aberrant skipping of exon 7 (and sometimes also exon 6), indicating that the exonic splicing enhancer at this position is required for normal inclusion of exon 7 and affects splicing of the adjacent upstream exon. Reproduced by genomic minigene transfection in vitro. Minigene transfection in cells, RT-PCR splicing analysis, silent mutation comparison Human mutation Medium 18273899
2007 Two synonymous mutations in PDHA1 exon 5 (c.483C>T and c.498C>T) disrupt a putative SRp55 binding exonic splicing enhancer, causing exon 5 skipping. Restoration of the perfect 5' splice site consensus by site-directed mutagenesis corrected the splicing defect in minigene transfection assays, confirming the functional role of this ESE. Minigene transfection in COS-7 and HeLa cells, RT-PCR, site-directed mutagenesis of 5' splice site, in silico ESE analysis, emetine treatment to reveal NMD-sensitive transcripts Molecular genetics and metabolism Medium 18023225
1997 The proximal 187 bp of the Pdha-2 promoter (core promoter) is sufficient for testis-specific, stage-specific expression in transgenic mice. CpG methylation within this core promoter, specifically at the ATF/CREB element, represses transcriptional activity; in vitro methylation of the ATF/CREB CpG abolishes promoter activity. Mutations within the ATF/CREB element reduce activity to ~50% of wild-type. Transgenic mice with Pdha-2 promoter deletions, CpG methylation analysis, in vitro methylation of promoter constructs followed by transfection, DNase I footprinting, ATF/CREB site mutagenesis Molecular and cellular biology High 9001214
2003 A pathogenic D296E (Asp-to-Glu) substitution in PDHA1 E1α was demonstrated to abolish pyruvate dehydrogenase activity by expression studies in E1α-null fibroblasts. Comparison with known E1 crystal structures suggests that D296 participates in a structurally critical interaction in the enzyme active site. Expression of mutant D296E PDHA1 cDNA in E1α-null fibroblast cell lines, PDH activity assay, structural comparison with E1 crystal structures Human mutation Medium 14635113
2010 PDH E1α deficiency in rat brain (induced by scAAV8-siRNA knockdown in striatum and substantia nigra) results in decreased expression of E1β and E2 subunits in addition to E1α, reduced PDC enzymatic activity, and reproducible neurological dysfunction (rotational asymmetry), establishing a causal relationship between E1α levels and complex assembly/activity in vivo. Stereotaxic delivery of scAAV8-siRNA targeting PDHA1 in rat brain, PDC subunit expression by immunoblotting, PDC activity assay, rotational behavior testing Molecular genetics and metabolism Medium 20685142
2022 SHP2 associates with PDHA1 in adipocytes (demonstrated by immunofluorescence, immunoprecipitation, and in-silico protein-protein interaction modeling). The SHP2-PDHA1-ROS regulatory axis is required for adipocyte maintenance, differentiation program, and IL-6 secretion. PDHA1 activity in pancreatic cancer cells promotes their growth response to adipocyte-conditioned media, and PDHA1 inhibition suppresses this effect. Co-immunoprecipitation, immunofluorescence co-localization, in-silico protein-protein interaction modeling, pharmacological inhibition of SHP2 and PDHA1, ROS measurements, conditioned media experiments with cancer cells Journal of cell communication and signaling Low 36074246
2025 Sarcosine reduces PDHA1 phosphorylation by interacting with PDK4, thereby enhancing pyruvate dehydrogenase activity and increasing mitochondrial ROS generation, promoting ferroptosis in lung adenocarcinoma. Sarcosine-enhanced PDH activity contributes to a metabolic shift from glycolysis to oxidative phosphorylation. Metabolomic profiling, 15N-labeled metabolic flux, seahorse metabolic assays, PDK4 interaction assays, PDHA1 phosphorylation measurement, lipid-ROS/MDA/ferrous iron measurements, patient-derived organoids 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 165 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 153 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 71 12662309
2018 miR‑21‑5p targets PDHA1 to regulate glycolysis and cancer progression in gastric cancer. Oncology reports 69 30226598
2001 Inactivation of the murine pyruvate dehydrogenase (Pdha1) gene and its effect on early embryonic development. Molecular genetics and metabolism 69 11708858
2015 The PI3K/Akt Pathway Regulates Oxygen Metabolism via Pyruvate Dehydrogenase (PDH)-E1α Phosphorylation. Molecular cancer therapeutics 60 25995437
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 57 37056926
2019 SIRT3 elicited an anti-Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis. Cancer medicine 57 30993888
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
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 46 34288231
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
2015 The oncoprotein HBXIP promotes glucose metabolism reprogramming via downregulating SCO2 and PDHA1 in breast cancer. Oncotarget 45 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 40 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
2009 Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency. Clinical genetics 33 20002461
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 33 14729417
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
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
2008 Neonatal pyruvate dehydrogenase deficiency due to a R302H mutation in the PDHA1 gene: MRI findings. Pediatric radiology 26 18197404
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
2017 Alteration of mitochondrial protein PDHA1 in Lewy body disease and PARK14. Biochemical and biophysical research communications 24 28564592
2006 Females with PDHA1 gene mutations: a diagnostic challenge. Mitochondrion 24 16713755
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
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 23 29104034
2006 Acute flaccid paralysis as initial symptom in 4 patients with novel E1alpha mutations of the pyruvate dehydrogenase complex. Neuropediatrics 23 16967364
1999 Dichloroacetate stabilizes the mutant E1alpha subunit in pyruvate dehydrogenase deficiency. Neurology 23 10449128
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
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
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
2025 Cholangiocarcinoma PDHA1 succinylation suppresses macrophage antigen presentation via alpha-ketoglutaric acid accumulation. Nature communications 19 40180922
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
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
2023 Effects of UBE3A on Cell and Liver Metabolism through the Ubiquitination of PDHA1 and ACAT1. Biochemistry 13 36920305
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
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 13 12231176
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 12 37055163
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
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
2025 Exosomal miR-21-5p from glioma associated mesenchymal stem cells promotes the progression and glycolysis of glioblastoma via PDHA1. Scientific reports 11 39833311
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
2019 Differential phenotypic expression of a novel PDHA1 mutation in a female monozygotic twin pair. Human genetics 11 31673819
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
2024 RNF4 mediated degradation of PDHA1 promotes colorectal cancer metabolism and metastasis. NPJ precision oncology 10 39521913
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
2023 Artificial intelligence reveals dysregulation of osteosarcoma and cuproptosis-related biomarkers, PDHA1, CDKN2A and neutrophils. Scientific reports 9 36967449
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 Sarcosine sensitizes lung adenocarcinoma to chemotherapy by dual activation of ferroptosis via PDK4/PDHA1 signaling and NMDAR-mediated iron export. Experimental hematology & oncology 8 40275333
2023 PDHA1 Alleviates Myocardial Ischemia-Reperfusion Injury by Improving Myocardial Insulin Resistance During Cardiopulmonary Bypass Surgery in Rats. Cardiovascular drugs and therapy 8 37610688
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 8 34869073
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
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 8 26038479
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
2003 A pathogenic glutamate-to-aspartate substitution (D296E) in the pyruvate dehydrogenase E1 subunit gene PDHA1. Human mutation 8 14635113
2025 PLK1-mediated PDHA1 phosphorylation drives metabolic reprogramming in lung cancer. Oncogene 7 40957950
2024 Manifestations of X-linked pyruvate dehydrogenase complex deficiency in female PDHA1 carriers. European journal of neurology 7 38497591
2022 SHP2 regulates adipose maintenance and adipocyte-pancreatic cancer cell crosstalk via PDHA1. Journal of cell communication and signaling 7 36074246
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 PDHA1-mediated H3K18 lactylation is involved in arsenic-induced nonalcoholic fatty liver disease by activating the CD36-NLRP3 inflammasome axis. Journal of hazardous materials 5 40961697

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