Lms1 is a Novel Protein Critical for Mitochondrial Maintenance

描述（由申请人提供）：骨骼肌线粒体功能障碍具有破坏性后果，包括肌肉萎缩，运动不耐受和胰岛素抵抗。我们已经发现了一种新的，高度保守的蛋白质对于维持酵母和哺乳动物细胞的线粒体功能和细胞能量稳态至关重要。我们将这种蛋白质命名为寿命相关线粒体应激反应1 （Lms1）。我们从酵母中获得的数据支持一种模型，即Lms1将泛素蛋白酶体系统的组分招募到线粒体中提取受损蛋白质并将其呈现给蛋白酶体进行降解。本研究的目的是通过培养的肌肉细胞和Lms1敲除小鼠来确定Lms1在骨骼肌中的作用功能和机制。对于跨越K99和R00期的Specific Aims 1和2，候选人将研究Lms1在培养肌肉细胞中的作用。Aim 1的研究将确定哺乳动物Lms1是否将泛素蛋白酶体系统招募到线粒体，作为线粒体蛋白质量控制系统的一部分。Aim 2中的研究将确定肌肉细胞中Lms1缺失所观察到的线粒体缺陷的性质。完成K99阶段提出的子目标将为候选人提供独立完成R00阶段所需的细胞和分子生物学方面的培训。对于特定目标3和4，候选人将确定Lms1在哺乳动物机体水平上的作用。对于Aim 3 （K99期），候选人将检查Lms1敲除小鼠心肌中的线粒体功能障碍，并开始骨骼肌的研究。对于Aim 4 （R00期），候选人将检查Lms1骨骼肌特异性敲除小鼠的线粒体功能障碍及其后果，包括运动不耐受、肌肉萎缩和胰岛素抵抗。在Aim 3中提出的实验将为候选人提供在R00阶段独立完成Aim 4所需的线粒体生理学训练。总的来说，这些实验试图建立Lms1在培养肌肉细胞中作用的机制基础，并将这些发现扩展到小鼠身上，在那里它们将被测试生理相关性。这些研究将为骨骼肌线粒体的调控提供新的见解。

DESCRIPTION (provided by applicant): Mitochondrial dysfunction in skeletal muscle has devastating consequences including muscle wasting, exercise intolerance, and insulin resistance. We have discovered that a novel, highly conserved protein is critical for maintenance of mitochondrial function and cellular energy homeostasis in yeast and mammalian cells. We have designated this protein Lifespan-associated Mitochondrial Stress-responsive 1 (Lms1). Our data from yeast support a model whereby Lms1 recruits components of the ubiquitin proteasome system to mitochondria to extract damaged proteins and present them to the proteasome for degradation. The purpose of this research is to determine the function and mechanism of Lms1 action in skeletal muscle using cultured muscle cells and Lms1 knockout mice. For Specific Aims 1 and 2, which span the K99 and R00 phases, the candidate will investigate the role of Lms1 in cultured muscle cells. Studies in Aim 1 will determine whether mammalian Lms1 recruits the ubiquitin proteasome system to mitochondria as part of a mitochondrial protein quality control system. Studies in Aim 2 will determine the nature of mitochondrial defects observed with Lms1 depletion in muscle cells. Completion of the sub- aims proposed during the K99 phase will provide the candidate with training in aspects of cellular and molecular biology necessary to independently complete the R00 phase. For Specific Aims 3 and 4, the candidate will determine the role of Lms1 at the mammalian organismal level. For Aim 3 (K99 phase), the candidate will examine an Lms1 knockout mouse for mitochondrial dysfunction in heart muscle and begin studies in skeletal muscle. For Aim 4 (R00 phase), the candidate will examine an Lms1 skeletal muscle- specific knockout mouse for mitochondrial dysfunction and consequences including exercise intolerance, muscle wasting, and insulin resistance. Experiments proposed in Aim 3 will provide the candidate with the training in mitochondrial physiology necessary to independently complete Aim 4 during the R00 phase. Collectively, these experiments seek to establish a mechanistic basis for Lms1 action in cultured muscle cells and to extend these findings to mice where they will be tested for physiologic relevance. These studies will provide novel insight into the regulation of mitochondria in skeletal muscle.