Loss Of Rubicon Ameliorates Doxorubicin-induced Cardiotoxicity

Doxorubicin(DOX)is one of the most potent chemotherapeutic agents in the treatment of malignancies.However,its therapeutic potential is limited by cardiotoxicity.Increased reactive oxygen species derived from damaged mitochondria has been considered as one of the major mediators of DOX cardiotoxicity.In this study,we test the hypothesis that loss of Rubicon,an inhibitory interacting partner of autophagy protein UVRAG,attenuates DOX-induced cardiotoxicity through improving mitochondrial quality.A mouse model of acute DOX-induced cardiotoxicity was established by a single intraperitoneal injection of DOX at a dose of 20 mg/kg.Rubicon expression was reduced in the hearts 16 h after DOX treatment.Loss of Rubicon improved survival in DOX-treated animals.Histopathological analysis showed that DOX-induced accumulation of cytoplasmic vacuolization and collagen was markedly diminished in the hearts from Rubicon-deficient mice.In addition,DOX-induced increase in serum activities of lactate dehydrogenase and myocardial muscle creatine kinase,two specific markers for cardiac damage,were attenuated by Rubicon deficiency.Enhanced ROS levels and reduced ATP content in myocardium caused by DOX were alleviated in Rubicon-deficient mice.Echocardiography showed that left ventricular posterior wall thinning,which occurred in DOX-treated WT mice,was not evident in DOX-treated Rubicon-deficient mice.Electron microscopy revealed that loss of Rubicon ameliorated DOX-induced mitochondrial damage in the hearts.We showed that loss of Rubicon rescued impaired autophagic flux induced by DOX in the hearts.Moreover,Parkin-mediated mitophagy,which was impaired in DOX-treated WT animals,was maintained in Rubicon-deficient mice.Additionally,loss of Rubicon prevented alterations in mitochondrial fusion and fission markers after DOX treatment.Collectively,our data suggest that loss of Rubicon mitigates DOX-induced cardiotoxicity through enhancement of mitochondrial quality by improving mitophagy and mitochondrial fission/fusion dynamics.Rubicon may be utilized as a potential molecular target for the prevention and therapy of DOX cardiotoxicity.