A conserved module required for mitochondrial function and viability under stress

描述（由申请人提供）：进行性线粒体氧化损伤和功能障碍是许多人类疾病发病机制的基础。使用酵母模型系统，我们已经表明，新的蛋白质寿命相关的线粒体应激反应1（Lms 1）的线粒体应激条件下招募到线粒体。当Lms 1耗尽时，氧化应激诱导呼吸功能丧失，并随着时间的推移显著加速活力丧失。Lms 1在体内与Cdc 48相关，Cdc 48是一种与内质网蛋白质逆转录移位和降解（ERAD途径）不可或缺的ATP酶。这些观测结果已推广到C. elegans，其中Lms 1的敲低导致过氧化物敏感性和寿命降低，并且氧化应激诱导胞质溶胶向线粒体易位。我们建议，LMS 1是一个重要的泛真核系统的氧化应激和线粒体功能障碍的致死性影响的保护的组成部分。我们推测，它的传感器线粒体压力，并通过Cdc 48招聘，制定错误折叠或损坏的线粒体蛋白质的降解。因此，我们提出确定：I）调节Lms 1线粒体易位的机制。我们将确定：1）线粒体功能障碍信号的位置和特异性; 2）该信号如何被中继到Lms 1;和3）Lms 1线粒体受体的身份。II）Lms 1在保持线粒体活性和活力中的功能。我们将：1）全面鉴定Lms 1-Cdc 48复合物的组分; 2）确定Lms 1-Cdc 48相互作用的性质和调节; 3）理解在lms 1突变体中观察到的线粒体缺陷。III）哺乳动物中的Lms 1调节和功能。我们将：1）使用培养的细胞检查哺乳动物Lms 1调节和功能;和2）使用Lms 1-/-小鼠，确定该蛋白在维持线粒体功能中的生理作用，特别是在心肌细胞中。 公共卫生相关性：许多人类疾病是由线粒体功能的进行性恶化引起的。我们已经发现了一个广泛的细胞系统，可以防止这种类型的恶化，并已表明它可以保护酵母和线虫免受某些类型的损害。我们认为，这将是同样重要的人类，并建议进一步了解其生化和生理作用。

DESCRIPTION (provided by applicant): Progressive mitochondrial oxidative damage and dysfunction is fundamental to the pathogenesis of many human diseases. Using a yeast model system, we have shown that the novel protein Lifespan-associated Mitochondrial Stress-responsive 1 (Lms1) is recruited to mitochondria under conditions of mitochondrial stress. When Lms1 is depleted, oxidative stress induces loss of respiratory function and markedly accelerated loss of viability over time. Lms1 associates in vivo with Cdc48, an ATPase integral to the retrotranslocation and degradation of proteins from the endoplasmic reticulum (ERAD pathway). These observations have been extended to C. elegans, wherein knockdown of Lms1 leads to peroxide sensitivity and decreased lifespan and oxidative stress induces cytosol to mitochondria translocation. We propose that Lms1 is a component of an important pan-eukaryotic system for protection from the lethal effects of oxidative stress and mitochondrial dysfunction. We hypothesize that it senses mitochondrial stress and, through Cdc48 recruitment, enacts the degradation of misfolded or damaged mitochondrial protein. We hereby propose to determine: I) The mechanisms regulating Lms1 mitochondrial translocation. We will determine: 1) the location and specificity of the mitochondrial dysfunction signal; 2) how this signal is relayed to Lms1; and 3) the identity of the Lms1 mitochondrial receptor. II) The function of Lms1 in preserving mitochondrial activity and viability. We will: 1) comprehensively identify the components of the Lms1- Cdc48 complex; 2) determine the nature and regulation of the Lms1-Cdc48 interaction; and 3) understand the mitochondrial defect observed in the lms1 mutant. III) Lms1 regulation and function in mammals. We will: 1) examine mammalian Lms1 regulation and function using cultured cells; and 2) using an Lms1-/- mouse, determine the physiological role of this protein in maintaining mitochondrial function, particularly in cardiomyocytes. PUBLIC HEALTH RELEVANCE: Many human diseases are caused by a progressive deterioration of the function of mitochondria. We have discovered a widespread cellular system that acts to prevent this type of deterioration and have shown that it protects both yeast and nematodes from certain types of damage. We suggest that it will be equally important in humans and propose to further understand its biochemical and physiological role.