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Modeling drug-induced mitochondrial toxicity with human primary cardiomyocytes

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Abstract

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 (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 mitochondrial 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.

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Acknowledgement

This work was 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), and the National Key Research and Development Program of China (2022YFA1104500).

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  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

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

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

    Zengwu Wang

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

    Li Wang & Bingying Zhou

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  1. Xiaoli Tang
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Tang, X., Liu, H., Rao, R. et al. Modeling drug-induced mitochondrial toxicity with human primary cardiomyocytes. Sci. China Life Sci. 67, 301–319 (2024). https://doi.org/10.1007/s11427-023-2369-3

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