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 

机构地区：[1]State Key Laboratory of Cardiovascular Disease,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100037,China [2]Department of Epidemiology,Cardiovascular Institute and Fuwai Hospital,Chinese Academy of Medical Science&Peking Union Medical College,Beijing 100037,China [3]Shenzhen Key Laboratory of Cardiovascular Disease,Fuwai Hospital Chinese Academy of Medical Sciences,Shenzhen,Shenzhen 518020,China

出　　处：《Science China(Life Sciences)》2024年第2期301-319,共19页中国科学（生命科学英文版）

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)。

摘　　要：Mitochondrial toxicity induced by therapeutic drugs is a major contributor for cardiotoxicity,posing a serious threat to pharmaceutical industries and patients’lives.However,mitochondrial toxicity testing is not incorporated into routine cardiac safety screening procedures.To 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 PCMs.Accordingly,action potential duration was elongated in h PCMs,reflecting clinical incidences of RDV-induced QT prolongation.In a screen for mitochondrial protectants,we identified mitochondrial ROS as a primary mediator of RDV-induced cardiotoxicity.Our 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.

关 键 词：remdesivir mitochondrial toxicity CARDIOTOXICITY human primary cardiomyocytes high-throughput screening 

分 类 号：R96[医药卫生—药理学]