Vms1 is a Novel Protein Critical for Mitochondrial Maintenance

Vms1 是一种对线粒体维护至关重要的新型蛋白质

• 批准号: 8711284
• 负责人: Eric B Taylor
• 金额: $ 24.4万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-08 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711284
• 关键词: Biological Models; Caenorhabditis elegans; Cell physiology; Cells; Characteristics; Complex; Coupling; Data; Defect; Electron Microscopy; Electron Transport; Exercise; Exercise Tolerance; Exhibits; Goals; Homeostasis; Hydrogen Peroxide; Insulin; Insulin Resistance; Knockout Mice; Link; Lipid Peroxidation; Longevity; Maintenance; Mammalian Cell; Membrane Potentials; Mitochondria; Mitochondrial Proteins; Modeling; Molecular and Cellular Biology; Mus; Muscle; Muscle Cells; Myocardium; Nature; Oxygen Consumption; Phase; Phenotype; Physiological; Physiology; Proteins; Proteome; Quality Control; Recruitment Activity; Regulation; Research; Respiratory Chain; Respiratory Failure; Role; Skeletal Muscle; Stress; System; Testing; Training; Ubiquitin; Yeasts; base; glucose uptake; in vivo; insight; insulin sensitivity; mitochondrial dysfunction; mitochondrial membrane; multicatalytic endopeptidase complex; muscle strength; novel; protein complex; protein degradation; public health relevance; research study; respiratory; wasting

Project Summary 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.

项目摘要 骨骼肌中线粒体功能障碍具有毁灭性后果，包括肌肉浪费， 运动不耐受和胰岛素抵抗。我们发现一种新颖的高度保守蛋白是 维持酵母中线粒体功能和细胞能量稳态至关重要 哺乳动物细胞。我们已经指定了这种蛋白质寿命相关的线粒体应力响应性1 （LMS1）。我们来自酵母的数据支持LMS1募集泛素组件的模型 蛋白酶体系统至线粒体提取受损蛋白质并将其呈现给蛋白酶体 降解。这项研究的目的是确定LMS1动作的功能和机制 使用培养的肌肉细胞和LMS1基因敲除小鼠的骨骼肌。对于特定目标1和2， 跨越K99和R00阶段，候选人将研究LMS1在培养的肌肉细胞中的作用。 AIM 1的研究将确定哺乳动物LMS1是否招募了泛素蛋白酶体系统 线粒体作为线粒体蛋白质质量控​​制系统的一部分。 AIM 2的研究将决定 肌肉细胞中LMS1耗竭观察到的线粒体缺陷的性质。完成子的完成 在K99阶段提出的目的将为候选人提供细胞和细胞方面的培训 独立完成R00期所需的分子生物学。对于特定目标3和4 候选人将确定LMS1在哺乳动物生物水平上的作用。对于目标3（K99阶段）， 候选人将检查一只LMS1敲除鼠标，以了解心肌的线粒体功能障碍并开始 骨骼肌研究。对于AIM 4（R00相），候选人将检查LMS1骨骼肌 - 针对线粒体功能障碍的特定基因敲除小鼠，以及包括运动不耐受的后果， 肌肉浪费和胰岛素抵抗。 AIM 3中提出的实验将为候选人提供 在R00期间独立完成AIM 4所需的线粒体生理培训 阶段。总的来说，这些实验试图在培养的LMS1作用中建立机械基础 肌肉细胞并将这些发现扩展到将对生理相关性进行测试的小鼠。这些 研究将为骨骼肌中线粒体调节提供新的见解。