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Lms1 is a Novel Protein Critical for Mitochondrial Maintenance

Lms1 是一种对线粒体维持至关重要的新型蛋白质

基本信息

批准号：
7869748
负责人：
Eric B Taylor
金额：
$ 9万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7869748
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 Knock-out 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

项目摘要

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.

描述(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。我们发现，在酵母和哺乳动物细胞中，一种新的高度保守的蛋白质对维持线粒体功能和细胞能量稳态至关重要。我们将该蛋白命名为与寿命相关的线粒体应激反应1(LMS1)。我们来自酵母的数据支持这样一个模型，即LMS1将泛素蛋白酶体系统的组件招募到线粒体中，以提取受损的蛋白质，并将它们呈现给蛋白酶体进行降解。本研究的目的是利用培养的肌细胞和Lms1基因敲除小鼠来确定Lms1在骨骼肌中的作用及其机制。对于跨越K99和R00阶段的特定目标1和2，候选人将研究LMS1在培养的肌肉细胞中的作用。目标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，作为线粒体蛋白质质量控制系统的一部分。AIM 2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。在K99阶段提出的子目标的完成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。对于特定的目标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Lms1基因敲除小鼠的心肌线粒体功能障碍，并开始骨骼肌研究。对于AIM 4(R00阶段)，候选人将检查Lms1骨骼肌特异基因敲除小鼠的线粒体功能障碍和后果，包括运动不耐受、肌肉萎缩和胰岛素抵抗。目标3中提出的实验将为候选人提供必要的线粒体生理学培训，以在R00阶段独立完成目标4。总的来说，这些实验试图为LMS1在培养的肌肉细胞中的作用建立一个机制基础，并将这些发现推广到老鼠身上，在那里他们将接受生理相关性测试。这些研究将为骨骼肌中线粒体的调控提供新的见解。