Mutations in Fis1 disrupt orderly disposal of defective mitochondria.
Mutations in Fis1 disrupt orderly disposal of defective mitochondria.
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DOI：
10.1091/mbc.e13-09-0525
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发表时间：
2014-01
影响因子：
3.3
通讯作者：
van der Bliek AM
中科院分区：
文献类型：
--
作者：
Shen Q;Yamano K;Head BP;Kawajiri S;Cheung JT;Wang C;Cho JH;Hattori N;Youle RJ;van der Bliek AM
线粒体分裂蛋白Drp1与线粒体上的MFf结合，然后进入内质网-线粒体界面上与Fis1的复合体。当应激引起分裂时，FIS1的突变会扰乱有缺陷的线粒体的处理。因此，FIS1与MFF顺序作用，将线粒体分裂与下游降解过程结合起来。在后生动物中，线粒体分裂是由动力蛋白相关蛋白Drp1介导的。线粒体外膜蛋白MFf将Drp1从胞浆募集到线粒体。第二种线粒体外膜蛋白，命名为FIS1，以前被认为是招募因子，但FIS1−/−细胞有轻微的或没有线粒体分裂缺陷。在这里，我们表明FIS1仍然是后生动物细胞线粒体分裂复合体的一部分。在分裂周期中，Drp1首先与线粒体表面的Mff结合，然后进入一个包含Fis1和内质网(ER)蛋白的复合体。FIS1的突变通常不会影响分裂，但当特定的线粒体毒素被用来诱导分裂时，它们可以扰乱下游的降解事件。FIS1突变引起的破坏导致了大的Lc3聚集体的积累。我们得出结论，FIS1可以在内质网-线粒体界面上与MFF顺序作用，将应激诱导的线粒体分裂与下游的降解过程结合起来。
The mitochondrial fission protein Drp1 binds to Mff on mitochondria, followed by entry into a complex with Fis1 at the ER–mitochondrial interface. Mutations in Fis1 disrupt disposal of defective mitochondria when fission is induced by stress. Fis1 thus acts in sequence with Mff to couple mitochondrial fission with downstream degradation processes. Mitochondrial fission is mediated by the dynamin-related protein Drp1 in metazoans. Drp1 is recruited from the cytosol to mitochondria by the mitochondrial outer membrane protein Mff. A second mitochondrial outer membrane protein, named Fis1, was previously proposed as recruitment factor, but Fis1−/− cells have mild or no mitochondrial fission defects. Here we show that Fis1 is nevertheless part of the mitochondrial fission complex in metazoan cells. During the fission cycle, Drp1 first binds to Mff on the surface of mitochondria, followed by entry into a complex that includes Fis1 and endoplasmic reticulum (ER) proteins at the ER–mitochondrial interface. Mutations in Fis1 do not normally affect fission, but they can disrupt downstream degradation events when specific mitochondrial toxins are used to induce fission. The disruptions caused by mutations in Fis1 lead to an accumulation of large LC3 aggregates. We conclude that Fis1 can act in sequence with Mff at the ER–mitochondrial interface to couple stress-induced mitochondrial fission with downstream degradation processes.