ArticleBlood advances2023
Mitochondrial pyruvate dehydrogenase kinases contribute to platelet function and thrombosis in mice by regulating aerobic glycolysis.
Article in Blood advances, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 37 citations in OpenAlex.
- Article
- Systemic metabolic dysfunction drives platelet-mediated inflammation, fibrogenesis, and hepatocarcinogenesis in metabolic dysfunction-associated steatotic liver disease.Clinical and molecular hepatology · 2026Review
- Research progress on neutrophil extracellular traps in sepsis‑induced coagulopathy (Review).Molecular medicine reports · 2026Review
- Targeting Endothelial PDK4-EndoMT Feedback Loop Mitigates the Development of Thoracic Aortic Dissection in Mice.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- Developing and validating a lactate-to-albumin ratio-enhanced score for mortality prediction in ICU patients with acute pulmonary embolism: a multi-cohort study.Frontiers in medicine · 2026Article
- Restricting metabolic plasticity enhances stress adaptation through the modulation of PDH and HIF1A in TRAP1-depleted colon cancer.Cancer letters · 2025Article
- Deleting ACC1 in platelets alters phospholipidome and reduces platelet activation and thrombosis in mice.Blood advances · 2025Article
- Mitochondrial Calcium Uniporter Regulates ITAM-Dependent Platelet Activation.Circulation research · 2025Article
- Analysis of Phenotypic and Molecular Variability of Memory-like NK Cells for Cancer Adoptive Cell Therapy Screening.Cancers · 2025Article
- Metabolic pathways in deep vein thrombosis: a new frontier for therapeutic intervention.Blood · 2025Review
- Platelets and diseases: signal transduction and advances in targeted therapy.Signal transduction and targeted therapy · 2025Review
- Platelet Extracellular Vesicles as Natural Delivery Vehicles for Mitochondrial Dysfunction Therapy?ACS biomaterials science & engineering · 2025Review
- IRAP Drives Ribosomal Degradation to Refuel Energy for Platelet Activation during Septic Thrombosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- α-Actinin-1 deficiency in megakaryocytes causes low platelet count, platelet dysfunction, and mitochondrial impairment.Blood advances · 2025Article
- Emerging Targets, Novel Directions, and Innovative Approaches in Thrombosis Therapy.Aging and disease · 2025Review
- The Mechanisms of Sepsis Induced Coagulation Dysfunction and Its Treatment.Journal of inflammation research · 2025Review
- The impact of glycolysis on ischemic stroke: from molecular mechanisms to clinical applications.Frontiers in neurology · 2025Review
- Inflammation and platelet hyperresponsiveness in coronary artery disease and the influence of Talin-1/αIIbβ3-mediated bidirectional signaling pathway.Frontiers in pharmacology · 2025Article
- Dynamic regulation of neutrophil immunometabolism by platelet-derived metabolites.Frontiers in immunology · 2025Review
- Metabolic insights into the warfarin-mango interaction: A pilot study integrating clinical observations and metabolomics.ADMET & DMPK · 2025Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Resting platelets rely on oxidative phosphorylation (OXPHOS) and aerobic glycolysis (conversion of glucose to lactate in the presence of oxygen) for their energy requirements. In contrast, platelet activation exhibits an increased rate of aerobic glycolysis relative to OXPHOS. Mitochondrial enzymes pyruvate dehydrogenase kinases (PDKs) phosphorylate the pyruvate dehydrogenase (PDH) complex to inhibit its activity, thereby diverting the pyruvate flux from OXPHOS to aerobic glycolysis upon platelet activation. Of 4 PDK isoforms, PDK2 and PDK4 (PDK2/4) are predominantly associated with metabolic diseases. Herein, we report that the combined deletion of PDK2/4 inhibits agonist-induced platelet functions, including aggregation, integrin αIIbβ3 activation, degranulation, spreading, and clot retraction. In addition, collagen-mediated PLCγ2 phosphorylation and calcium mobilization were significantly reduced in PDK2/4-/- platelets, suggesting impaired GPVI signaling. The PDK2/4-/- mice were less susceptible to FeCl3-induced carotid and laser-induced mesenteric artery thrombosis without any effect on hemostasis. In adoptive transfer experiments, thrombocytopenic hIL-4Rα/GPIbα-transgenic mice transfused with PDK2/4-/- platelets exhibited less susceptibility to FeCl3 injury-induced carotid thrombosis compared with hIL-4Rα/GPIbα-Tg mice transfused with WT platelets, suggesting a platelet-specific role of PDK2/4 in thrombosis. Mechanistically, the inhibitory effects of PDK2/4 deletion on platelet function were associated with reduced PDH phosphorylation and glycoPER in activated platelets, suggesting that PDK2/4 regulates aerobic glycolysis. Finally, using PDK2 or PDK4 single KO mice, we identified that PDK4 plays a more prominent role in regulating platelet secretion and thrombosis compared with PDK2. This study identifies the fundamental role of PDK2/4 in regulating platelet functions and identifies the PDK/PDH axis as a potentially novel antithrombotic target.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.