Persistent mitochondrial hyperfusion promotes G2/M accumulation and caspase-dependent cell death.
Persistent mitochondrial hyperfusion promotes G2/M accumulation and caspase-dependent cell death.
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DOI：
10.1371/journal.pone.0091911
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
MacKeigan JP
中科院分区：
文献类型：
--
作者：
Westrate LM;Sayfie AD;Burgenske DM;MacKeigan JP
癌细胞具有定义其肿瘤行为的几个标志。一个是它们不减的复制潜力，允许细胞持续增殖，从而有助于增加肿瘤负荷。细胞在细胞周期中的进展受到一系列检查点的调节，这些检查点确保遗传信息以及各种细胞成分（包括细胞器和蛋白质复合物）成功传递到两个产生的子细胞。线粒体网状物经历协调的形状变化，以对应于细胞周期的特定阶段，最引人注目的是胞质分裂之前的线粒体完全碎裂。为了确定线粒体分裂是否是确保线粒体适当分离成两个子细胞所需的步骤，我们研究了线粒体动力学对细胞周期进程的重要性。我们发现，线粒体过度融合促进细胞周期进展的缺陷，其特征在于细胞不能退出G2/M。此外，持续的线粒体融合的延长时间导致强有力的半胱天冬酶依赖性细胞死亡。细胞死亡信号通过caspase-8的激活和切割来协调，促进有效的死亡反应。这些结果证明了线粒体动力学在细胞周期进程中的重要性，并且抑制线粒体裂变调节剂可以提供靶向癌细胞的复制潜力的治疗策略。
Cancer cells have several hallmarks that define their neoplastic behavior. One is their unabated replicative potential that allows cells to continually proliferate, and thereby contribute to increasing tumor burden. The progression of a cell through the cell cycle is regulated by a series of checkpoints that ensures successful transmission of genetic information, as well as various cellular components, including organelles and protein complexes to the two resulting daughter cells. The mitochondrial reticulum undergoes coordinated changes in shape to correspond with specific stages of the cell cycle, the most dramatic being complete mitochondrial fragmentation prior to cytokinesis. To determine whether mitochondrial fission is a required step to ensure proper mitochondrial segregation into two daughter cells, we investigated the importance of mitochondrial dynamics to cell cycle progression. We found that mitochondrial hyperfusion promotes a defect in cell cycle progression characterized by an inability for cells to exit G2/M. Additionally, extended periods of persistent mitochondrial fusion led to robust caspase-dependent cell death. The cell death signals were coordinated through activation and cleavage of caspase-8, promoting a potent death response. These results demonstrate the importance of mitochondrial dynamics in cell cycle progression, and that inhibiting mitochondrial fission regulators may provide a therapeutic strategy to target the replicative potential of cancer cells.
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影响因子：
3.7
作者：
Looyenga BD;Hutchings D;Cherni I;Kingsley C;Weiss GJ;Mackeigan JP
通讯作者：
Mackeigan JP
DOI：
10.1083/jcb.201210045
发表时间：
2013-06-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Strack S;Wilson TJ;Cribbs JT
通讯作者：
Cribbs JT
DOI：
10.1126/science.1219855
发表时间：
2012-08-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Youle RJ;van der Bliek AM
通讯作者：
van der Bliek AM
影响因子：
6
作者：
Masuda, A;Maeno, K;Takahashi, T
通讯作者：
Takahashi, T
影响因子：
5.2
作者：
Chang CR;Blackstone C
通讯作者：
Blackstone C