Enhanced mitophagy mediated by the YAP/Parkin pathway protects against DOX-induced cardiotoxicity

The clinical usage of Doxorubicin (DOX) is limited due to its cardiotoxicity. Although the precise mechanism remains unclear, there is an increasing body of evidence that has demonstrated that mitophagy is responsible for DOX-induced cardiotoxicity. In the present study, Parkin, a key protein for mitophagy initiation, was revealed to be downregulated in mouse hearts and in H9c2 cells upon DOX treatment. Enforced expression of Parkin led to mitophagy activation and attenuated cell apoptosis in H9c2 cells. Parkin transgenic mice inhibited DOX-induced cardiotoxicity. Furthermore, Yes-associatd protein, as a transcription co-activator, regulated the gene expression of Parkin, and in turn Parkin overexpression protected against cell apoptosis induced by DOX treatment. Taken together, enhanced mitophagy mediated by YAP/Parkin pathway protects against DOX-induced cardiotoxicity in mouse heart. These studies revealed the complex pathological process of DOX-induced cardiotoxicity and provided novel insight into potential chemotherapy targets.