ROLE OF MGM1P IN MITOCHONDRIAL DYNAMICS

维持正常的线粒体形态和线粒体DNA(MtDNA)对大多数真核细胞的生存至关重要。尽管线粒体形态、拷贝数和线粒体DNA含量的变化与多种人类疾病和衰老过程有关，但人们对控制线粒体行为的分子机制知之甚少。这项建议的长期目标是了解在萌芽酵母酿酒酵母中，Mgm1p GTP酶在维持野生型线粒体动力学中所起的作用。MGM1的突变破坏了野生型线粒体的形态，导致线粒体DNA丢失，并减少了线粒体在分裂过程中向子细胞的运输。在这个应用中，我建议：L)产生和分析一组新的MGM1(mgm1-ts)温度敏感等位基因，2)分离和分析mgm1-ts等位基因的第二位点抑制物，以及3)克隆和鉴定由这些第二位点抑制物定义的基因和蛋白质。这些实验将确定对功能重要的MGLP结构域，还将确定与MGM1在同一遗传途径中发挥作用的新基因。由于人类细胞表达一种mgm1p同源物，了解mgmlp在酵母中的功能最终将有助于深入了解哺乳动物细胞中的线粒体行为。

Maintenance of normal mitochondrial morphology and mitchondrial DNA (mtDNA) is critical for the survival of most eukaryotic cells. Although changes in mitochondrial morphology, copy number and mtDNA content are associated with a variety of human diseases and the aging process, little is known about the molecular mechanisms that control aspects of mitochondrial behavior. The long-term objective os this proposal is to understand the role the Mgm1p GTPase plays in sustaining wild-type mitochondrial dynamics in the budding yeast, Saccharomyces cerevisiae. Mutations in MGM1 disrupt wild-type mitochondrial morphology, induce mtDNA loss and reduce the transport of mitochondria to daughter cells during division. In this application I propose: l) to generate and analyze a panel of novel temperature-sensitive alleles of MGM1 (mgml-ts), 2) to isolate and analyze second-site suppressors of mgml-ts alleles, and 3) to clone and characterize the genes and proteins defined by these second-site suppressors. These experiments will identify Mgmlp domains important for function and will also identify new genes that act in the same genetic pathway as MGM1. Since human cells express an Mgm1p homologue, understanding Mgmlp function in yeast should ultimately provide insight into mitochondrial behavior in mammalian cells.