Msp1/ATAD1: mitochondrial and peroxisomal protein sorting

 描述(申请人提供)：线粒体在细胞生物学的许多方面发挥着非常重要的作用，线粒体功能障碍导致了大多数与年龄相关的人类疾病。正如预期的那样，有许多系统致力于在压力下维持线粒体的功能。我们最近发现了一种AAA ATPase，它是正常提取错位到线粒体的蛋白质所必需的，特别是那些具有单一C-末端跨膜结构域(尾部-锚定)的蛋白质。当这种蛋白质，在酵母中被命名为Msp1，在哺乳动物中被命名为ATAD1时，细胞表现出线粒体呼吸功能的进行性丧失。本项目的目标是：1)利用酵母系统确定底物识别和提取的机制；2)确定ATAD1是否对于维持小鼠心脏的线粒体功能是必需的；3)检测线粒体功能对患有尾部锚定蛋白表达异常和进行性神经退行性疾病患者的影响；4)以Msp1/ATAD1作为模型蛋白，用于询问线粒体从线粒体到过氧化物酶体泡运输的机制和重要性；以及5)研究Msp1/ATAD1在限制过氧化异体蛋白在过氧体生物发生受损的条件下的线粒体定位中的作用，如Zellweger综合征。

 DESCRIPTION (provided by applicant): Mitochondria play a very important role in many aspects of cellular biology and mitochondrial dysfunction contributes to most age--‐related human diseases. As expected, there are a number of systems dedicated to maintaining mitochondrial function under stress. We recently identified an AAA ATPase that is required for the normal extraction of proteins that mislocalize to mitochondria, specifically those that have a single C--‐terminal transmembrane domain (tail--‐anchored). When this protein, named Msp1 in yeast and ATAD1 in mammals, is absent, cells exhibit progressive loss of mitochondrial respiratory function. The goals of this project are to: 1) define the mechanisms of substrate recognition and extraction using the yeast system; 2) determine whether ATAD1 is required for the maintenance of mitochondrial function in the mouse heart; 3) examine the impact of mitochondrial function on a patient with aberrant tail--‐anchored protein expression and a progressive neurodegenerative disease; 4) use Msp1/ATAD1 as a model protein by which to interrogate the mechanisms and importance of mitochondria--‐to--‐peroxisome vesicular trafficking; and 5) examine the role of Msp1/ATAD1 in limiting mitochondrial localization of peroxisomal proteins in conditions of impaired peroxisomal biogenesis, such as Zellweger syndrome.