Modeling drug-induced mitochondrial toxicity with human primary cardiomyocytes

作     者：Xiaoli Tang Hong Liu Rongjia Rao Yafei Huang Mengqi Dong Miaomiao Xu Shanshan Feng Xun Shi Li Wang Zengwu Wang Bingying Zhou 

作者机构：State Key Laboratory of Cardiovascular DiseaseFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100037China Department of EpidemiologyCardiovascular Institute and Fuwai HospitalChinese Academy of Medical Science&Peking Union Medical CollegeBeijing 100037China Shenzhen Key Laboratory of Cardiovascular DiseaseFuwai Hospital Chinese Academy of Medical SciencesShenzhenShenzhen 518020China 

出 版 物：《Science China(Life Sciences)》 (中国科学（生命科学英文版）)

年 卷 期：2024年第67卷第2期

页      面：301-319页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-1-I2M-006,2023-I2M-1-003,2022-I2M-2-001,2021-1-I2M-019) the National Natural Science Foundation of China(82070287,82088101 and 82025004) the National Key Research and Development Program of China(2022YFA1104500) 

主　　题：remdesivir mitochondrial toxicity cardiotoxicity human primary cardiomyocytes high-throughput screening 

摘      要：Mitochondrial toxicity induced by therapeutic drugs is a major contributor for cardiotoxicity,posing a serious threat to pharmaceutical industries and patients’***,mitochondrial toxicity testing is not incorporated into routine cardiac safety screening *** accurately model native human cardiomyocytes,we comprehensively evaluated mitochondrial responses of adult human primary cardiomyocytes(h PCMs)to a nucleoside analog,remdesivir(RDV).Comparison of their response to human pluripotent stem cell-derived cardiomyocytes revealed that the latter utilized a mitophagy-based mitochondrial recovery response that was absent in h ***,action potential duration was elongated in h PCMs,reflecting clinical incidences of RDV-induced QT *** a screen for mitochondrial protectants,we identified mitochondrial ROS as a primary mediator of RDV-induced *** study demonstrates the utility of h PCMs in the detection of clinically relevant cardiac toxicities,and offers a framework for h PCM-based high-throughput screening of cardioprotective agents.