ArticleInflammation2024
Inhibition of Pyruvate Dehydrogenase Kinase 4 Protects Cardiomyocytes from lipopolysaccharide-Induced Mitochondrial Damage by Reducing Lactate Accumulation.
Article in Inflammation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
- PDK4-Associated Metabolic Reprogramming Contributes to Lactate Accumulation and Parthanatos-Related Changes in Septic Cardiomyocytes.Cardiovascular drugs and therapy · 2026Article
- Beyond the Pump: Unravelling Immunometabolic Crosstalk and Organelle Dynamics in Sepsis-Induced Cardiomyopathy.Journal of cardiovascular translational research · 2026Article
- S2P-modified PLGA bifunctional nanodrug: inhibiting vascular senescence and foam cell formation for atherosclerosis treatment.Journal of nanobiotechnology · 2026Article
- Article
- A novel mouse model of adenine-supplemented high-fat diet induced cardiovascular-kidney-metabolic syndrome.Hypertension research : official journal of the Japanese Society of Hypertension · 2026Article
- Targeting Endothelial PDK4-EndoMT Feedback Loop Mitigates the Development of Thoracic Aortic Dissection in Mice.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- Association between lactate-to-calcium ratio and 28-day mortality in patients with sepsis-induced myocardial injury: a retrospective cohort study based on the MIMIC-IV database.International journal of emergency medicine · 2026Article
- Synergistic therapeutic impact of dichloroacetate nanoparticles and doxorubicin in modulating pyruvate dehydrogenase kinase in breast carcinoma model.Scientific reports · 2026Article
- Lactate and lactylation in sepsis: regulation of immune-metabolic crosstalk and organ injury.Frontiers in immunology · 2026Review
- Mitochondrial regulation of lactylation in sepsis-induced cardiomyopathy.Critical care (London, England) · 2025Review
- Mitochondria at the Heart of Sepsis: Mechanisms, Metabolism, and Sex Differences.International journal of molecular sciences · 2025Review
- Mechanism analysis and intervention strategies of the inflammatory microenvironment in traumatic spinal cord injury.Frontiers in immunology · 2025Review
- Sepsis-induced changes in pyruvate metabolism: insights and potential therapeutic approaches.EMBO molecular medicine · 2024Review
- PCAT19: the role in cancer pathogenesis and beyond.Frontiers in cell and developmental biology · 2024Review
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Mitochondrial dysfunction is considered one of the major pathogenic mechanisms of sepsis-induced cardiomyopathy (SIC). Pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of mitochondrial metabolism, is essential for maintaining mitochondrial function. However, its specific role in SIC remains unclear. To investigate this, we established an in vitro model of septic cardiomyopathy using lipopolysaccharide (LPS)-induced H9C2 cardiomyocytes. Our study revealed a significant increase in PDK4 expression in LPS-treated H9C2 cardiomyocytes. Inhibiting PDK4 with dichloroacetic acid (DCA) improved cell survival, reduced intracellular lipid accumulation and calcium overload, and restored mitochondrial structure and respiratory capacity while decreasing lactate accumulation. Similarly, Oxamate, a lactate dehydrogenase inhibitor, exhibited similar effects to DCA in LPS-treated H9C2 cardiomyocytes. To further validate whether PDK4 causes cardiomyocyte and mitochondrial damage in SIC by promoting lactate production, we upregulated PDK4 expression using PDK4-overexpressing lentivirus in H9C2 cardiomyocytes. This resulted in elevated lactate levels, impaired mitochondrial structure, and reduced mitochondrial respiratory capacity. However, inhibiting lactate production reversed the mitochondrial dysfunction caused by PDK4 upregulation. In conclusion, our study highlights the pathogenic role of PDK4 in LPS-induced cardiomyocyte and mitochondrial damage by promoting lactate production. Therefore, targeting PDK4 and its downstream product lactate may serve as promising therapeutic approaches for treating SIC.
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Registered trials
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