α-ketoglutarate protects against septic cardiomyopathy by improving mitochondrial mitophagy and fission

Septic cardiomyopathy is a considerable complication in sepsis, which has high mortality rates and an incompletely understood pathophysiology, which hinders the development of effective treatments. alpha-ketoglutarate (AKG), a component of the tricarboxylic acid cycle, serves a role in cellular metabolic regulation. The present study delved into the therapeutic potential and underlying mechanisms of AKG in ameliorating septic cardiomyopathy. A mouse model of sepsis was generated and treated with AKG via the drinking water. Cardiac function was assessed using echocardiography, while the mitochondrial ultrastructure was examined using transmission electron microscopy. Additionally, in vitro, rat neonatal ventricular myocytes were treated with lipopolysaccharide (LPS) as a model of sepsis and then treated with AKG. Mitochondrial function was evaluated via ATP production and Seahorse assays. Additionally, the levels of reactive oxygen species were determined using dihydroethidium and chloromethyl derivative CM-H2DCFDA staining, apoptosis was assessed using a TUNEL assay, and the expression levels of mitochondria-associated proteins were analyzed by western blotting. Mice subjected to LPS treatment exhibited compromised cardiac function, reflected by elevated levels of atrial natriuretic peptide, B-type natriuretic peptide and beta-myosin heavy chain. These mice also exhibited pronounced mitochondrial morphological disruptions and dysfunction in myocardial tissues; treatment with AKG ameliorated these changes. AKG restored cardiac function, reduced mitochondrial damage and corrected mitochondrial dysfunction. This was achieved primarily through increasing mitophagy and mitochondrial fission. In vitro, AKG reversed LPS-induced cardiomyocyte apoptosis and dysregulation of mitochondrial energy metabolism by increasing mitophagy and fission. These results revealed that AKG administration mitigated cardiac dysfunction in septic cardiomyopathy by promoting the clearance of damaged mitochondria by increasing mitophagy and fission, underscoring its therapeutic potential in this context.