Endoplasmic reticulum selective autophagy alleviates anthracycline-induced cardiotoxicity

Abstract

Abstract Unfolded protein response (UPR) plays a critical role for preventing death of cardiomyocytes induced by excessive endoplasmic reticulum (ER) in response to cytotoxicity of anthracycline antineoplastic drugs through mitigating misfoled proteins accumulation in the hearts. Here, we demonstrate that ER-selective autophagy (ER-phagy) serves as a salvage system which enable cardiomyocytes to survive even if UPR fails to restore ER stress induced by doxorubicin (Dox), an anthracycline drug, by using in-house developed monitoring systems to evaluate the activity of ER-phagy in cardiomyocytes. Notably, ER-phagy contributes to relieving cardiac damage induced by Dox administration and is mediated by CCPG1, an ER-phagy receptor protein. Furthermore, ablation of CCPG1 abolished ER-phagy and worsened Dox-induced cardiac damage by inducing excessive ER stress-associated apoptosis. Our data highlight a compensatory role of CCPG1-driven ER-phagy in reducing Dox toxicity and pose a potential therapeutic target to intervene against Dox induced cardiomyopathy.