Mitochondrial fission promotes radiation-induced increase in intracellular Ca2+ level leading to mitotic catastrophe in mouse breast cancer EMT6 cells
Mitochondrial fission promotes radiation-induced increase in intracellular Ca2+ level leading to mitotic catastrophe in mouse breast cancer EMT6 cells
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DOI：
10.1016/j.bbrc.2019.11.027
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发表时间：
2020-01-29
影响因子：
3.1
通讯作者：
Inanami, Osamu
中科院分区：
文献类型：
--
作者：
Bo, Tomoki;Yamamori, Tohru;Inanami, Osamu
线粒体动力学对于细胞在各种应激下的存活至关重要。以前，我们报告说，Drp 1促进线粒体分裂后，X射线照射和其抑制导致细胞辐射敏感性降低和有丝分裂灾难。然而，辐射诱导的有丝分裂灾难与线粒体分裂的机制仍不清楚。在这项研究中，我们研究了EMT 6细胞有丝分裂灾难中细胞ATP产生，ROS产生和Ca 2+水平的参与。敲除线粒体分裂调节因子Drp 1和Fis 1，导致线粒体延长，细胞放射敏感性显著减弱。线粒体分裂减少主要减少有丝分裂灾难，而不是辐射后的坏死和凋亡。在Drp 1和Fis 1基因敲除的细胞中，细胞内ATP含量与对照细胞相似。N-乙酰半胱氨酸和2-吡喃葡萄糖苷抗坏血酸对辐射后的有丝分裂灾难没有影响。照射后细胞内[Ca ~（2+）]i升高，抑制Drp 1和Fis 1可完全抑制[Ca ~（2+）]i升高。此外，BAPTA-AM显着减少辐射诱导的有丝分裂灾难，表明细胞内Ca 2+是辐射后有丝分裂灾难诱导的关键介质。这些结果表明，线粒体分裂与辐射诱导的有丝分裂灾难通过胞质Ca 2+调节。(C)2019爱思唯尔公司All rights reserved.
Mitochondrial dynamics are crucial for cellular survival in response to various stresses. Previously, we reported that Drp1 promoted mitochondrial fission after x-irradiation and its inhibition resulted in reduced cellular radiosensitivity and mitotic catastrophe. However, the mechanisms of radiation-induced mitotic catastrophe related to mitochondrial fission remain unclear. In this study, we investigated the involvement of cellular ATP production, ROS generation, and Ca2+ levels in mitotic catastrophe in EMT6 cells. Knockdown of Drp1 and Fis1, which are mitochondrial fission regulators, resulted in elongated mitochondria and significantly attenuated cellular radiosensitivity. Reduced mitochondrial fission mainly decreased mitotic catastrophe rather than necrosis and apoptosis after irradiation. Cellular ATP contents in Drp1 and Fis1 knockdown cells were similar to those in control cells. N-acetylcysteine and 2-glucopyranoside ascorbic acid have no effect on mitotic catastrophe after irradiation. The cellular [Ca2+]i level increased after irradiation, which was completely suppressed by Drp1 and Fis1 inhibition. Furthermore, BAPTA-AM significantly reduced radiation-induced mitotic catastrophe, indicating that cellular Ca2+ is a key mediator of mitotic catastrophe induction after irradiation. These results suggest that mitochondrial fission is associated with radiation-induced mitotic catastrophe via cytosolic Ca2+ regulation. (C) 2019 Elsevier Inc. All rights reserved.