Human mitochondrial Fis1 links to cell cycle regulators at G2/M transition
Human mitochondrial Fis1 links to cell cycle regulators at G2/M transition
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DOI：
10.1007/s00018-013-1428-8
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发表时间：
2014-02-01
影响因子：
8
通讯作者：
Cho, Hyeseong
中科院分区：
文献类型：
--
作者：
Lee, Seungmin;Park, Yong-Yea;Cho, Hyeseong
我们以前已经表明，延长线粒体延长触发细胞衰老。在这里，我们报道了通过hFis 1缺失导致的线粒体延长导致细胞周期进展通过G2/M期的严重缺陷（类似于有丝分裂指数的3倍减少; p < 0.01）。Myc-hFis 1的重新引入到这些细胞中诱导线粒体断裂并恢复细胞周期，表明线粒体的形态动力学变化与细胞周期密切相关。在hFis 1敲低细胞中，控制G2/M期的细胞周期调节因子，包括细胞周期蛋白A、细胞周期蛋白B1、细胞周期蛋白依赖性激酶1（Cdk 1）、polo样激酶1（Plk 1）、极光激酶A和Mad 2，被显著抑制（2- 10倍）。然而，值得注意的是，当通过hFis 1和Opa 1的双重敲低诱导线粒体片段化时，细胞恢复了进入有丝分裂的能力，并且细胞周期调节剂反弹。重建的细胞周期蛋白B1/Cdk 1复合物，G2/M转换的主要调节器，未能恢复有丝分裂进入hFis 1耗尽的细胞。与此相反，Plk 1，一个上游调控的细胞周期蛋白B1/Cdk 1复合物，或FoxM 1（叉头框M1），一个主转录因子的G2/M期的细胞周期调控因子的表达，恢复了这些细胞的细胞周期。我们的研究结果表明，线粒体分裂分子hFis 1通过与细胞周期机制的相互作用来确保适当的细胞分裂。
We have previously shown that prolonged mitochondrial elongation triggers cellular senescence. Here, we report that enforced mitochondrial elongation by hFis1 depletion caused a severe defect in cell cycle progression through G2/M phase (similar to 3-fold reduction in mitotic index; p < 0.01). Reintroduction of Myc-hFis1 to these cells induced mitochondrial fragmentation and restored the cell cycle, indicating that morphodynamic changes of mitochondria closely link to the cell cycle. In hFis1-knockdown cells, cell cycle regulators governing the G2/M phase, including cyclin A, cyclin B1, cyclin-dependent kinase1 (Cdk1), polo-like kinase1 (Plk1), aurora kinase A and Mad2, were significantly suppressed (2- to 10-fold). Notably, however, when mitochondrial fragmentation was induced by double knockdown of hFis1 and Opa1, the cells regained their ability to enter mitosis, and cell cycle regulators were rebounded. Reconstitution of the cyclin B1/Cdk1 complex, a major regulator of the G2/M transition, failed to restore mitotic entry in hFis1-depleted cells. In contrast, expression of Plk1, an upstream regulator of the cyclin B1/Cdk1 complex, or FoxM1 (forkhead box M1), a master transcriptional factor for the cell cycle regulators of G2/M phase, restored the cell cycle in these cells. Our findings suggest that mitochondrial fission molecule hFis1 ensures the proper cell division by interplay with the cell cycle machinery.