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Mitochondrial Sirtuins and Doxorubicin-induced Cardiotoxicity

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Abstract

Doxorubicin (DOX) is the most effective and extensively used treatment for many tumors. However, its clinical use is hampered by its cardiotoxicity. DOX-induced mitochondrial dysfunction, which causes reactive oxygen species (ROS) generation, cardiomyocyte death, bioenergetic failure, and decreased cardiac function, is a very important mechanism of cardiotoxicity. These cellular processes are all linked by mitochondrial sirtuins (SIRT3–SIRT4). Mitochondrial sirtuins preserve mitochondrial function by increasing mitochondrial metabolism, inhibiting ROS generation by activating the antioxidant enzyme manganese-dependent superoxide dismutase (MnSOD), decreasing apoptosis by activating the forkhead homeobox type O (FOXO) and P53 pathways, and increasing autophagy through AMP-activated protein kinase (AMPK)/mTOR signaling. Thus, sirtuins function at the control point of many mechanisms involved in DOX-induced cardiotoxicity. In this review, we focus on the role of mitochondrial sirtuins in mitochondrial biology and DOX-induced cardiotoxicity. A further aim is to highlight other mitochondrial processes, such as autophagy (mitophagy) and mitochondrial quality control (MQC), for which the effect of mitochondrial sirtuins on cardiotoxicity is unknown.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81760065 to J. Li) and the Jiangxi Natural Science Foundation (20151BB-G70166 to J. Li).

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  1. Ling He and Fuxiang Liu are co-first author of this work.

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  1. Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Minde Road No. 1, Nanchang of Jiangxi, 330006, China

    Ling He, Fuxiang Liu & Juxiang Li

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He, L., Liu, F. & Li, J. Mitochondrial Sirtuins and Doxorubicin-induced Cardiotoxicity. Cardiovasc Toxicol 21, 179–191 (2021). https://doi.org/10.1007/s12012-020-09626-x

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