ArticleJournal of leukocyte biology2020
Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes.
Article in Journal of leukocyte biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 42 citations in OpenAlex.
- Itaconate and its derivatives in human health and diseases.Signal transduction and targeted therapy · 2026Review
- DADA Enhances CD8Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Microglial Innate Immune Memory: Implications and Research Advances in Central Nervous System Disorders.Current issues in molecular biology · 2026Review
- The Pyruvate Dehydrogenase Complex: A 90-Year-Old Enigma Shaping the Future of Structural Enzymology.Advances in experimental medicine and biology · 2026Review
- Review
- Itaconic Acid: A Regulator of Immune Responses and Inflammatory Metabolism.Current issues in molecular biology · 2025Review
- Mitochondria at the Heart of Sepsis: Mechanisms, Metabolism, and Sex Differences.International journal of molecular sciences · 2025Review
- Immunometabolic Effect of Nitric Oxide on Human Macrophages Challenged With the SARS-CoV2-Induced Cytokine Storm. A Fluxomic Approach.Advanced healthcare materials · 2025Article
- Metabolic specialization drives reduced pathogenicity in Pseudomonas aeruginosa isolates from cystic fibrosis patients.PLoS biology · 2024Article
- The Values of PDK1 and LDH Levels in Patients with Sepsis and Septic Shock: A Prospective Observational Study.Journal of inflammation research · 2024Article
- Metabolite itaconate in host immunoregulation and defense.Cellular & molecular biology letters · 2023Review
- Preclinical Study in Mouse Thymus and Thymocytes: Effects of Treatment with a Combination of Sodium Dichloroacetate and Sodium Valproate on Infectious Inflammation Pathways.Pharmaceutics · 2023Article
- Glutathionylation of pyruvate dehydrogenase complex E2 and inflammatory cytokine production during acute inflammation are magnified by mitochondrial oxidative stress.Redox biology · 2023Article
- Early hyperlipidemia triggers metabolomic reprogramming with increased SAH, increased acetyl-CoA-cholesterol synthesis, and decreased glycolysis.Redox biology · 2023Article
- Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation.Cell reports · 2023Article
- Pyruvate dehydrogenase kinase regulates macrophage polarization in metabolic and inflammatory diseases.Frontiers in immunology · 2023Review
- Sepsis, pyruvate, and mitochondria energy supply chain shortage.Journal of leukocyte biology · 2022Review
- Dichloroacetate improves systemic energy balance and feeding behavior during sepsis.JCI insight · 2022Article
- Metabolic Regulation of Macrophage Activation.Journal of innate immunity · 2022Review
- Persistent hyperammonia and altered concentrations of urea cycle metabolites in a 5-day swine experiment of sepsis.Scientific reports · 2021Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
The pyruvate dehydrogenase complex (PDC)/pyruvate dehydrogenase kinase (PDK) axis directs the universal survival principles of immune resistance and tolerance in monocytes by controlling anabolic and catabolic energetics. Immune resistance shifts to immune tolerance during inflammatory shock syndromes when inactivation of PDC by increased PDK activity disrupts the tricarboxylic acid (TCA) cycle support of anabolic pathways. The transition from immune resistance to tolerance also diverts the TCA cycle from citrate-derived cis-aconitate to itaconate, a recently discovered catabolic mediator that separates the TCA cycle at isocitrate and succinate dehydrogenase (SDH). Itaconate inhibits succinate dehydrogenase and its anabolic role in mitochondrial ATP generation. We previously reported that inhibiting PDK in septic mice with dichloroacetate (DCA) increased TCA cycle activity, reversed septic shock, restored innate and adaptive immune and organ function, and increased survival. Here, using unbiased metabolomics in a monocyte culture model of severe acute inflammation that simulates sepsis reprogramming, we show that DCA-induced activation of PDC restored anabolic energetics in inflammatory monocytes while increasing TCA cycle intermediates, decreasing itaconate, and increasing amino acid anaplerotic catabolism of branched-chain amino acids (BCAAs). Our study provides new mechanistic insight that the DCA-stimulated PDC homeostat reconfigures the TCA cycle and promotes anabolic energetics in monocytes by reducing levels of the catabolic mediator itaconate. It further supports the theory that PDC is an energy sensing and signaling homeostat that restores metabolic and energy fitness during acute inflammation.
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Registered trials
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.