Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
Mol Biol Cell. 2014 Jan;25(1):145-59. doi: 10.1091/mbc.E13-09-0525. Epub 2013 Nov 6.
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.
线粒体的分裂是由真核生物中的与 dynamin 相关的蛋白 Drp1 介导的。Drp1 由细胞质通过线粒体的外膜蛋白 Mff 招募到线粒体。另一种线粒体的外膜蛋白，称为 Fis1，之前被认为是招募因子，但 Fis1(-/-)细胞仅有轻微或没有线粒体分裂缺陷。在这里，我们表明 Fis1 仍然是真核细胞中线粒体分裂复合物的一部分。在分裂周期中，Drp1 首先与线粒体表面的 Mff 结合，然后进入一个包括 Fis1 和内质网（ER）蛋白在内的复合物，该复合物位于 ER-线粒体界面。Fis1 中的突变通常不会影响分裂，但当使用特定的线粒体毒素诱导分裂时，它们可以破坏下游的降解事件。Fis1 突变引起的破坏导致大量 LC3 聚集物的积累。我们得出结论，Fis1 可以与 ER-线粒体界面处的 Mff 依次作用，将应激诱导的线粒体分裂与下游的降解过程偶联起来。
