"The mechanism of mitochondrial fission and fusion"

描述（由申请人提供）：线粒体是复杂的细胞器，其细胞作用超出了呼吸、脂肪和氨基酸代谢以及离子稳态的充分表征的代谢途径。他们的 在细胞中的中心作用反映在它们作为细胞凋亡的调节剂的事实上。线粒体也是动态的细胞器，不断地进行分裂和融合。利用酵母S.作为我们的实验系统，我们已经鉴定了线粒体分裂和融合直接需要的蛋白质，其在哺乳动物细胞中的直系同源物也调节细胞凋亡。其中有3种动力蛋白相关蛋白（DRPs），它们是在各种细胞过程中调节膜动力学的大的自组装GTP酶。到目前为止，我们的工作已经将这些关键参与者置于裂变和聚变期间发生的分子事件的框架中。我们建议在这些研究的基础上更详细地了解这些蛋白质如何合作进行膜裂变和融合的机制。为了实现这一目标，我们已经建立了体外试验，概括线粒体融合和线粒体裂变事件。我们将使用这些检测结合遗传学和细胞学方法来确定线粒体分裂和融合的分子机制。两个保守的人类线粒体融合蛋白的突变与神经退行性疾病Charcot-Marie-Tooth和显性视神经萎缩有关。解决线粒体分裂和融合的机制将有助于深入了解这些与融合蛋白相关的疾病的病因，并有助于了解线粒体动力学如何调节细胞凋亡。

DESCRIPTION (provided by applicant): Mitochondrial are complex organelles whose cellular roles extend beyond the well-characterized metabolic pathways of respiration, fatty-and amino-acid metabolism and ion homeostasis. Their central role in the cell is reflected by the fact that they function as regulators of apoptosis. Mitochondria are also dynamic organelles, which continually undergo fission and fusion. Using the yeast S. cerevisiae as our experimental system, we have identified proteins directly required for mitochondrial fission and fusion, whose orthologs in mammalian cells also regulate apoptosis. Among them are 3 dynamin-related proteins (DRPs), which are large self-assembling GTPases that regulate membrane dynamics in a variety of cellular processes. To date, our work has placed these key players into a framework of molecular events that occur during fission and fusion. We propose to build on these studies to understand in more detail the mechanism of how these proteins collaborate to carry out the mechanics of membrane fission and fusion. Towards this goal, we have established in vitro assays that recapitulate mitochondrial fusion and mitochondrial fission events. We will use these assays combined with genetic and cytological approaches to determine the molecular mechanism of mitochondrial fission and fusion. Mutations in 2 conserved human mitochondrial fusion proteins have been linked to the neurodegenerative diseases, Charcot-Marie-Tooth and dominant optic atrophy. Resolving the mechanisms of mitochondrial fission and fusion will provide insight into the etiology of these fusion protein-linked diseases and will help to understand how mitochondrial dynamics regulates apoptosis.