Msp1/ATAD1: mitochondrial and peroxisomal protein sorting

 描述（由申请人提供）：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功能。我们最近发现了一种AAA ATP酶，它是正常提取错误定位于线粒体的蛋白质所必需的，特别是那些具有单个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Msp 1，在哺乳动物中被命名为ATAD 1时，细胞表现出线粒体呼吸功能的逐渐丧失。该项目的目标是：1）确定使用酵母系统识别和提取底物的机制; 2）确定ATAD 1是否是维持小鼠心脏线粒体功能所必需的; 3）检查线粒体功能对具有异常尾锚定蛋白表达和进行性神经退行性疾病的患者的影响; 4）使用Msp 1/ATAD 1作为模型蛋白，通过其询问线粒体--至-过氧化物酶体囊泡运输的机制和重要性;和5）检查Msp 1/ATAD 1在过氧化物酶体生物发生受损的条件下（例如Zellweger综合征）限制过氧化物酶体蛋白的线粒体定位中的作用。

 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.