Fis1 Regulation of Mitochondrial Fission

项目摘要/摘要 线粒体分裂或分裂的改变会造成严重的后果，甚至死亡。然而，这样做的原因是 都是未知的。据推测，线粒体有自己的生命周期，涉及不健康的裂变 线粒体在一种称为有丝分裂的自噬过程中将它们移除。这些质量控制过程是 在萌芽酵母和人类之间进化保守，尽管最近在一定程度上 受到了质疑。在酵母中，分裂需要蛋白质FIS1，这种蛋白质现在被认为是分裂所必需的 在哺乳动物中，但对于有丝分裂来说是必不可少的。与这一观点一致的是有丝分裂中的FIS1相互作用 人类细胞培养。与这种观点相反，FIS1的丢失会拉长线粒体并取代分裂 线粒体中的机械酶Drp1在某些但不是所有的细胞类型中。一些进化上的突变 FIS1中的保守残基损害了分裂和Drp1的定位。不同保守残基的突变 破坏与有丝分裂中的一个关键接头的结合，Rab7 GTP酶激活蛋白TBC1D15和 TBC1D17。这些发现表明，FIS1在分裂和有丝分裂中都扮演着保守的角色。使用酵母- 受启发的突变，以及最先进的遗传、显微和结构工具，我们现在准备 确定保守成分如何支配线粒体在分裂、有丝分裂或吞噬之间的命运 细胞凋亡。为了了解支配这一过程的蛋白质-蛋白质相互作用，生化和结构研究 将与最先进的细胞生物学和遗传学方法相结合。更好地理解 蛋白质机制及其工作原理将确定未来研究中可能针对的调控关键点 用小分子来抑制，并激活分裂、有丝分裂和凋亡。这样的发现 分子最终可能导致对裂变活性增强或减弱的疾病的治疗 中心。

Project Summary/Abstract Altered division, or fission, of mitochondria has severe consequences even death. Yet the reasons for this are unknown. It is postulated that the mitochondria have their own lifecycle that involves fission of unhealthy mitochondria to remove them in an autophagic process called mitophagy. These quality control processes are evolutionarily conserved between budding yeast and humans, although extent to which has recently been called into question. In yeast, fission requires the protein FIS1 that is now thought to be dispensable for fission in mammals, but indispensable for mitophagy. Consistent with this view are FIS1 interactions in mitophagy human cell culture. Contrary to this view, loss of FIS1 elongates mitochondrial and displaces the fission mechanoenzyme DRP1 from mitochondria in some, but not all, cell types. Mutations to some evolutionarily conserved residues in FIS1 impair fission and DRP1 localization. Mutations to different conserved residues impair binding to a critical adaptor in mitophagy, the Rab7 GTPase Activating Proteins TBC1D15 and TBC1D17. These findings suggest that FIS1 is conserved for roles in both fission and mitophagy. Using yeast- inspired mutations, along with state-of-the-art genetic, microscopic, and structural tools, we are now poised to determine how conserved components govern the fate of mitochondria between fission, mitophagy, or apoptosis. To understand the protein-protein interactions that govern this, biochemical and structural studies will be integrated with state-of-the-art cell biological and genetic approaches. A better understanding of the protein machinery and how it works will identify key points of regulation that may be targeted in future studies with small molecules to inhibitor, and activate fission, mitophagy, and apoptosis. The discovery of such molecules may ultimately lead to treatments for diseases in which enhanced, or impaired, fission activity is central.