Doxorubicin-induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy
Doxorubicin-induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy
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DOI：
10.1096/fj.201802663r
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发表时间：
2019-10-01
期刊：
影响因子：
4.8
通讯作者：
Liang, Qiangrong
中科院分区：
文献类型：
--
作者：
Catanzaro, Michael P.;Weiner, Ashley;Liang, Qiangrong
多柔比星（Dox）是一种广泛使用的可引起心力衰竭的抗心律失常药物。Dox心脏毒性与线粒体损伤密切相关。线粒体分裂和线粒体自噬是质量控制机制，通常有助于维持健康的线粒体库。然而，不受控制的线粒体分裂和线粒体自噬可能损害心肌细胞的活力，使其易于细胞死亡。在这里，我们通过使用Dox处理的H9 c2心肌成肌细胞来测试这种可能性，该细胞表达靶向荧光蛋白MitoDsRed或新型双荧光线粒体自噬报告基因mt-Rosella。Dox诱导线粒体碎片化，如通过减小的形状因子、纵横比和平均线粒体大小所示。这种效应被短干扰RNA介导的动力蛋白相关蛋白1（DRP 1），一个主要的裂变调节基因敲低。重要的是，DRP 1敲低减少了细胞死亡，如碘化丙啶阳性细胞数量减少和胱天蛋白酶-3和聚（ADP-核糖）聚合酶裂解所示。此外，DRP 1缺陷小鼠受到保护，免受Dox诱导的心脏损伤，强烈支持DRP 1依赖性线粒体片段化在Dox心脏毒性中的作用。此外，Dox加速了线粒体自噬通量，这是由DRP 1敲低减弱，由线粒体自噬报告基因mt-Rosella评估，这表明在Dox诱导的线粒体自噬中线粒体片段化的必要性。敲低parkin（一种线粒体自噬的正调节因子），显著减少了Dox诱导的细胞死亡，而过表达parkin则产生相反的效果。总之，这些结果表明，Dox心脏毒性至少部分是由线粒体碎片化增加和溶酶体加速线粒体降解介导的。在生理范围内限制线粒体分裂和线粒体自噬的策略可能有助于减少Dox心脏毒性。卡坦扎罗湾P.，Weiner，A.，Kaminaris，A.，Li，C.，蔡文福，赵芳，小林，小林，黄，Y.，Sesaki，H.，梁，英-地多柔比星诱导的心肌细胞死亡是由未经检查的线粒体分裂和线粒体自噬介导的。
Doxorubicin (Dox) is a widely used antineoplastic agent that can cause heart failure. Dox cardiotoxicity is closely associated with mitochondrial damage. Mitochondrial fission and mitophagy are quality control mechanisms that normally help maintain a pool of healthy mitochondria. However, unchecked mitochondrial fission and mitophagy may compromise the viability of cardiomyocytes, predisposing them to cell death. Here, we tested this possibility by using Dox-treated H9c2 cardiac myoblast cells expressing either the mitochondria-targeted fluorescent protein MitoDsRed or the novel dual-fluorescent mitophagy reporter mt-Rosella. Dox induced mitochondrial fragmentation as shown by reduced form factor, aspect ratio, and mean mitochondrial size. This effect was abolished by short interference RNA-mediated knockdown of dynamin-related protein 1 (DRP1), a major regulator of fission. Importantly, DRP1 knockdown decreased cell death as indicated by the reduced number of propidium iodide-positive cells and the cleavage of caspase-3 and poly (ADP-ribose) polymerase. Moreover, DRP1-deficient mice were protected from Dox-induced cardiac damage, strongly supporting a role for DRP1-dependent mitochondrial fragmentation in Dox cardiotoxicity. In addition, Dox accelerated mitophagy flux, which was attenuated by DRP1 knockdown, as assessed by the mitophagy reporter mt-Rosella, suggesting the necessity of mitochondrial fragmentation in Dox-induced mitophagy. Knockdown of parkin, a positive regulator of mitophagy, dramatically diminished Dox-induced cell death, whereas overexpression of parkin had the opposite effect. Together, these results suggested that Dox cardiotoxicity was mediated, at least in part, by the increased mitochondrial fragmentation and accelerated mitochondrial degradation by the lysosome. Strategies that limit mitochondrial fission and mitophagy in the physiologic range may help reduce Dox cardiotoxicity.-Catanzaro, M. P., Weiner, A., Kaminaris, A., Li, C., Cai, F., Zhao, F., Kobayashi, S., Kobayashi, T., Huang, Y., Sesaki, H., Liang, Q. Doxorubicin-induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy.