Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China.
Department of Pediatrics, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China.
J Infect Dis. 2024 Apr 12;229(4):1178-1188. doi: 10.1093/infdis/jiad365.
Sepsis-induced cardiomyopathy (SIC) is a cardiac dysfunction caused by sepsis, with mitochondrial dysfunction being a critical contributor. Pyruvate dehydrogenase kinase 4 (PDK4) is a kinase of pyruvate dehydrogenase with multifaceted actions in mitochondrial metabolism. However, its role in SIC remains unknown.
Serum PDK4 levels were measured and analyzed in 27 children with SIC, 30 children with sepsis, and 29 healthy children. In addition, for mice exhibiting SIC, the effects of PDK4 knockdown or inhibition on the function and structure of the myocardium and mitochondria were assessed.
The findings from the analysis of children with SIC revealed that PDK4 was significantly elevated and correlated with disease severity and organ injury. Nonsurvivors displayed higher serum PDK4 levels than survivors. Furthermore, mice with SIC benefited from PDK4 knockdown or inhibition, showing improved myocardial contractile function, reduced myocardial injury, and decreased mitochondrial structural injury and dysfunction. In addition, inhibition of PDK4 decreased the inhibitory phosphorylation of PDHE1α (pyruvate dehydrogenase complex E1 subunit α) and improved abnormal pyruvate metabolism and mitochondrial dysfunction.
PDK4 is a potential biomarker for the diagnosis and prognosis of SIC. In experimental SIC, PDK4 promoted mitochondrial dysfunction with increased phosphorylation of PDHE1α and abnormal pyruvate metabolism.
脓毒症相关性心肌病（SIC）是由脓毒症引起的心脏功能障碍，线粒体功能障碍是其关键致病因素。丙酮酸脱氢酶激酶 4（PDK4）是丙酮酸脱氢酶的一种激酶，在线粒体代谢中具有多方面的作用。然而，其在 SIC 中的作用尚不清楚。
检测并分析 27 例 SIC 患儿、30 例脓毒症患儿和 29 例健康儿童的血清 PDK4 水平。此外，还评估了 PDK4 敲低或抑制对 SIC 小鼠心肌和线粒体功能及结构的影响。
SIC 患儿的分析结果显示，PDK4 水平显著升高，并与疾病严重程度和器官损伤相关。非幸存者的血清 PDK4 水平高于幸存者。此外，SIC 小鼠通过 PDK4 敲低或抑制获益，表现为心肌收缩功能改善、心肌损伤减轻、线粒体结构损伤和功能障碍减少。此外，PDK4 的抑制降低了 PDHE1α（丙酮酸脱氢酶复合物 E1 亚单位α）的抑制性磷酸化，并改善了异常的丙酮酸代谢和线粒体功能障碍。
PDK4 是 SIC 诊断和预后的潜在生物标志物。在实验性 SIC 中，PDK4 通过增加 PDHE1α 的磷酸化和异常的丙酮酸代谢促进线粒体功能障碍。
