Mitochondrial fusion: analysis of Fzo function

描述（申请人的描述）：线粒体是显著动态的 细胞器;它们经历融合和裂变的循环，在某些情况下， 对发展信号的反应。线粒体融合过程是独一无二的 在细胞内膜融合事件中，因为每个细胞器含有两个 脂质双层的集合。最近对酵母和苍蝇的研究已经确定了Fzo， 一种定位于线粒体的跨膜GTP酶，作为一种重要的分子， 线粒体融合此外，这些研究表明， 融合对于正常的呼吸功能是必要的。有趣的是，FZO包含 几个卷曲螺旋基序，让人想起病毒包膜蛋白和SNARE 复合物直接参与其他类型的膜融合。 关于线粒体融合的生理作用， 哺乳动物的发育此外，FZO促进 线粒体融合是未知的。本提案针对这些问题， 以下研究目标：（1）确定线粒体融合在 通过小鼠的发育和细胞分析研究哺乳动物的发育 缺乏Fzo的同源物，（2）获得结构的详细了解 Fzo的结构域和这些结构域在介导膜融合中的作用， (3)通过发展核聚变机器的其他组成部分， 体外线粒体融合测定和FZO相关的FZO-1蛋白的分离 proteins.除了澄清基本的细胞过程，这些研究可能 进一步了解人类线粒体疾病和衰老。

DESCRIPTION (Applicant's Description): Mitochondria are remarkably dynamic organelles; they undergo cycles of fusion and fission, in some cases in response to developmental signals. The mitochondrial fusion process is unique among intracellular membrane fusion events, because each organelle contains two sets of lipid bilayers. Recent studies in yeast and flies have identified Fzo, a transmembrane GTPase localized to niitochondria, as an essential molecule in mitochondrial fusion. Moreover, these studies indicate that mitochondrial fusion is essential for normal respiratory function. Intriguingly, Fzo contains several coiled-coil motifs, reminiscent of viral envelope proteins and SNARE complexes that are directly involved in other types of membrane fusion. Little is known about the physiological role of mitochondrial fusion in mammalian development. In addition, the mechanism through which Fzo promotes mitochondrial fusion is unknown. This proposal addresses these issues with the following research goals: (1) to determine the role of mitochondrial fusion in mammalian development through developmental and cellular analysis of mice lacking homologs of Fzo, (2) to gain a detailed understanding of the structural domains of Fzo and the roles these domains play in mediating membrane fusion, (3) to identify other components of the fusion machinery through development of an in vitro mitochondrial fusion assay and isolation of Fzo-associated proteins. In addition to clarifying a basic cellular process, these studies may further understanding of human mitochondrial diseases and aging.