Songorine inhibits mitophagy in chronic heart failure via the TBC1D15/Fis1/Rab7A pathway

BACKGROUND AND PURPOSE: Songorine (SGR) is an alkaloid extracted from Aconitum carichaelii Debx. and has a demonstrated role in cardiac dysfunction. Chronic heart failure (CHF) is a severe clinical syndrome leading to functional impairment and death, primarily due to the deterioration of energy metabolism in cardiomyocytes. However, the precise mechanisms responsible for SGR therapeutic effects in CHF are unclear. EXPERIMENTAL APPROACH: Transverse aortic constriction (TAC) surgery was adopted to mimic heart failure in mice. Matrix-assisted laser desorption/ionisation mass spectrum image (MALDI-MSI), in combination with tissue metabolomics, revealed the distribution of different metabolites in cardiac tissue. H9c2 cells were selected as a cell model for in vitro experiments. ROS content, mitochondrial membrane potential and lysosomal activity were measured in different experimental groups. KEY RESULTS: CHF mice exhibited cardiac dysfunction, mitochondrial damage and metabolic alterations after 4 weeks. Treatment with SGR significantly improved ejection fraction, decreased autophagic levels and affected the spatial distribution of fatty acylcarnitines, a series of metabolites associated with β-oxidation. These findings suggested that SGR possessed an ameliorative effect on pressure overload-induced CHF, potentially mitigating mitochondrial damage by modulating energy metabolism. SGR administration partially reversed these alterations and restored cardiac function, enhancing the phosphorylation of mTOR and potentially mitigating the separation of mitochondria and lysosomes via the TBC1D15/Fis1/Rab7A pathway. Finally, studies on the effects of siRNA further demonstrated the critical role of SGR in mitochondrial function. CONCLUSIONS AND IMPLICATIONS: This study provides valuable insights into the role of SGR in managing CHF via TBC1D15-mediated mitochondrial dysfunction.