MECHANISMS OF MITOCHONDRIAL FISSION AND FUSION

描述(申请人的描述)：线粒体形态的变化和 拷贝数与多种人类疾病有关，包括 神经紊乱和某些类型的癌症。虽然新陈代谢 线粒体的功能已被广泛研究，分子 调控线粒体膜动力学的机制尚不清楚。在……里面 在当前的资助期，我们描述了S. 调控线粒体形态和拷贝数的酿酒酵母。Dnm1p是一种 作用于线粒体膜外膜的动力蛋白相关GTP酶 管制裂变。Fzo1p(模糊洋葱)是一种跨膜GTP酶，调节 线粒体对接和/或融合。这两种GTP酶都有人类同源物， 当突变时，会导致线粒体形态的缺陷。这些发现 说明酵母如何有效地用作研究分子的工具 控制人类细胞线粒体动力学的机制。在下一次 在资助期内，我们将继续研究线粒体的分裂和融合 利用遗传、分子和生物化学方法相结合的酵母。 具体地说，我们建议：1)鉴定和鉴定SFZ基因/蛋白 线粒体分裂所必需的，2)确定Fzo1p的作用 线粒体融合中的自身相互作用，3)筛选结合伙伴 在其GTP结合状态下与Fzo1p相互作用，以及4)在体外形成 线粒体融合试验。我们提出的研究将提供新的 关于线粒体分裂的分子和生化基础的信息 并在真核细胞中融合。

DESCRIPTION (applicant's description): Changes in mitochondrial morphology and copy number are associated with a variety of human diseases including neurological disorders and some types of cancer. Although the metabolic functions of mitochondria have been extensively studied, the molecular mechanisms that regulate mitochondrial membrane dynamics are not understood. In the current funding period, we characterized two different GTPases in S. cerevisiae that regulate mitochondrial morphology and copy number. Dnm1p is a dynamin-related GTPase that acts on the outer mitochondrial membrane to regulate fission. Fzo1p (fuzzy onions) is a transmembrane GTPase that regulates mitochondrial docking and/or fusion. Both GTPases have human homologues that, when mutated, cause defects in mitochondrial morphology. These findings illustrate how effectively yeast can be used as a tool to study the molecular mechanisms that control mitochondrial dynamics in human cells. During the next funding period, we will continue to study mitochondrial fission and fusion in yeast using a combination of genetic, molecular and biochemical approaches. Specifically, we propose: 1) to identify and characterize SFZ genes/proteins required for mitochondrial fission, 2) to determine the role of Fzo1p self-interactions in mitochondrial fusion, 3) to screen for binding partners that interact with Fzo1p in its GTP-bound state, and 4) to develop an in vitro assay for mitochondrial fusion. The studies we propose will provide new information about the molecular and biochemical basis of mitochondrial fission and fusion in eukaryotic cells.