Sphingosylphosphorylcholine ameliorates doxorubicin-induced cardiotoxicity in zebrafish and H9c2 cells by reducing excessive mitophagy and mitochondrial dysfunction.

Doxorubicin (DOX, CHNO), is an anthracycline tumor chemotherapy drug, which has significant side effects on many organs including the heart. In recent years, mitochondrial dysfunction caused by DOX was identified as an important reason for cardiotoxic injury. Sphingosylphosphorylcholine (SPC) is essential for mitochondrial homeostasis in our previous report, however, its role in DOX-caused cardiomyopathy has remained elusive. Herein, DOX treated zebrafish embryos (90 μM) and adult fish (2.5 μM/g) were used to simulate DOX-induced cardiotoxic damage. Histopathological and ultrastructural observations showed that SPC (2.5 μM) significantly ameliorated DOX-induced pericardial edema, myocardial vacuolization and apoptosis. Furthermore, SPC (2.5 μM) can significantly inhibit DOX-induced apoptosis and promote cell proliferation in DOX treated H9c2 cells (1 μM), which is dependent on the restoration of mitochondrial homeostasis, including restored mitochondrial membrane potential, mitochondrial superoxide and ATP levels. We finally confirmed that SPC restored mitochondrial homeostasis through ameliorating DOX-induced excessive mitophagy. Mechanistically, SPC reduced calmodulin (CaM) levels and thus inhibiting Parkin activation and Parkin-dependent mitophagy. These results suggest that reducing the cardiotoxicity of chemotherapeutic drugs by targeting SPC may be a new solution to rescue chemotherapy injury.