首页|Modeling drug-induced mitochondrial toxicity with human primary cardiomyocytes

Modeling drug-induced mitochondrial toxicity with human primary cardiomyocytes

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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 cardlomyocytes,we comprehensively evaluated mitochondrial responses of adult human primary car-diomyocytes(hPCMs)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 hPCMs.Accordingly,action potential duration was elongated in hPCMs,reflecting clinical incidences of RDV-induced QT prolongation.In a screen for mi-tochondrial protectants,we identified mitochondrial ROS as a primary mediator of RDV-induced cardiotoxicity.Our study demonstrates the utility of hPCMs in the detection of clinically relevant cardiac toxicities,and offers a framework for hPCM-based high-throughput screening of cardioprotective agents.

remdesivirmitochondrial toxicitycardiotoxicityhuman primary cardiomyocyteshigh-throughput screening

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

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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

Shenzhen Key Laboratory of Cardiovascular Disease,Fuwai Hospital Chinese Academy of Medical Sciences,Shenzhen,Shenzhen 518020,China

Department of Epidemiology,Cardiovascular Institute and Fuwai Hospital,Chinese Academy of Medical Science & Peking Union Medical College,Beijing 100037,China

CAMS Innovation Fund for Medical Sciences(CIFMS)CAMS Innovation Fund for Medical Sciences(CIFMS)CAMS Innovation Fund for Medical Sciences(CIFMS)CAMS Innovation Fund for Medical Sciences(CIFMS)National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Key Research and Development Program of China

2021-1-I2M-0062023-I2M-1-0032022-I2M-2-0012021-1-I2M-0198207028782088101820250042022YFA1104500

2024

10.1007/s11427-023-2369-3

中国科学:生命科学(英文版)
中国科学院

中国科学:生命科学(英文版)

CSTPCD
影响因子：0.806
ISSN：1674-7305
年,卷(期)：2024.67(2)
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