Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
School of Professional Studies, Northwestern University, Chicago, IL, USA.
J Cell Mol Med. 2017 Dec;21(12):3394-3404. doi: 10.1111/jcmm.13250. Epub 2017 Jun 23.
The long-term usage of doxorubicin (DOX) is largely limited due to the development of severe cardiomyopathy. Many studies indicate that DOX-induced cardiac injury is related to reactive oxygen species generation and ultimate activation of apoptosis. The role of novel mitochondrial fission protein 1 (Mtfp1) in DOX-induced cardiotoxicity remains elusive. Here, we report the pro-mitochondrial fission and pro-apoptotic roles of Mtfp1 in DOX-induced cardiotoxicity. DOX up-regulates the Mtfp1 expression in HL-1 cardiac myocytes. Knockdown of Mtfp1 prevents cardiac myocyte from undergoing mitochondrial fission, and subsequently reduces the DOX-induced apoptosis by preventing dynamin 1-like (Dnm1l) accumulation in mitochondria. In contrast, when Mtfp1 is overexpressed, a suboptimal dose of DOX can induce a significant percentage of cells to undergo mitochondrial fission and apoptosis. These data suggest that knocking down of Mtfp1 can minimize the cardiomyocytes loss in DOX-induced cardiotoxicity. Thus, the regulation of Mtfp1 expression could be a novel therapeutic approach in chemotherapy-induced cardiotoxicity.
多柔比星（DOX）的长期使用受到严重心肌病发展的限制。许多研究表明，DOX 诱导的心脏损伤与活性氧的产生和最终的细胞凋亡激活有关。新型线粒体裂变蛋白 1（Mtfp1）在 DOX 诱导的心脏毒性中的作用仍不清楚。在这里，我们报告了 Mtfp1 在 DOX 诱导的心脏毒性中的促线粒体裂变和促凋亡作用。DOX 上调 HL-1 心肌细胞中 Mtfp1 的表达。Mtfp1 敲低可防止心肌细胞发生线粒体裂变，随后通过阻止 dynamin 1 样（Dnm1l）在线粒体中的积累，减少 DOX 诱导的细胞凋亡。相反，当 Mtfp1 过表达时，亚致死剂量的 DOX 可诱导相当比例的细胞发生线粒体裂变和凋亡。这些数据表明，敲低 Mtfp1 可最大限度地减少 DOX 诱导的心脏毒性中的心肌细胞损失。因此，调节 Mtfp1 的表达可能是化疗诱导的心脏毒性的一种新的治疗方法。
