PDK4-Associated Metabolic Reprogramming Contributes to Lactate Accumulation and Parthanatos-Related Changes in Septic Cardiomyocytes.

BACKGROUND

Sepsis-related myocardial injury (SRMI) is characterized by metabolic reprogramming and cardiomyocyte death, but the relationship between these processes remains unclear. This study investigated the association between pyruvate dehydrogenase kinase 4 (PDK4)-related metabolic dysregulation and parthanatos-related changes in SRMI.

METHODS

SRMI was modeled using cecal ligation and perforation in mice and lipopolysaccharide-stimulated H9c2 cells. Myocardial injury, metabolic alterations, mitochondrial dysfunction, and parthanatos-related changes were assessed using RNA sequencing, histopathology, transmission electron microscopy, biochemical assays, Western blotting, RT-qPCR, immunofluorescence, and flow cytometry. PDK4 was silenced using siRNA in LPS-stimulated H9c2 cells for functional validation.

RESULTS

PDK4 was significantly upregulated in septic myocardium. This change was accompanied by increased PDH phosphorylation, pyruvate and lactate accumulation, ATP depletion, and mitochondrial ultrastructural damage. PAR accumulation increased, NAD⁺ levels decreased, and AIF/MIF nuclear translocation was enhanced, indicating prominent parthanatos-related changes. In LPS-stimulated H9c2 cells, PDK4 knockdown decreased the p-PDH/PDH ratio and lactate levels while increasing ATP levels. PDK4 silencing also reduced PAR accumulation, increased NAD⁺ levels, and decreased AIF/MIF nuclear translocation.

CONCLUSION

PDK4 contributes to metabolic dysregulation and parthanatos-related changes in septic cardiomyocytes. However, whether lactate directly mediates the relationship between PDK4 and parthanatos requires further rescue experiments.