MECHANISMS OF MITOCHONDRIAL FISSION AND FUSION

描述（申请人描述）：线粒体形态学变化， 拷贝数与多种人类疾病相关，包括 神经系统疾病和某些癌症。虽然新陈代谢 线粒体的功能已被广泛研究， 调节线粒体膜动力学的机制尚不清楚。在 在当前的资助期内，我们描述了S. 酿酒酵母，调节线粒体形态和拷贝数。dnm 1 p是一个 动力蛋白相关的GT3，作用于线粒体外膜， 调节裂变。Fzo 1 p（fuzzy onions）是一种跨膜GTdR， 线粒体对接和/或融合。两种GTP酶都有人类同源物， 当突变时，导致线粒体形态缺陷。这些发现 说明如何有效地酵母可以作为一种工具来研究分子 控制人类细胞中线粒体动力学的机制。在下一个 在资助期间，我们将继续研究线粒体的裂变和融合， 酵母使用遗传，分子和生物化学方法的组合。 具体而言，我们提出：1）鉴定和表征SFZ基因/蛋白 线粒体分裂所需，2）确定Fzo 1 p的作用 线粒体融合中的自我相互作用，3）筛选结合伴侣 与GTP结合状态的Fzo 1 p相互作用，以及4）开发体外 线粒体融合测定。我们提出的研究将提供新的 关于线粒体分裂的分子和生物化学基础的信息 和真核细胞融合。

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.