Clu forms a dynamic new ribonucleoprotein particle directly involved in mitochondrial function

Clu 形成直接参与线粒体功能的动态新核糖核蛋白颗粒

基本信息

批准号：
10434693
负责人：
Rachel Tafel Cox
金额：
$ 32.41万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434693
关键词：
Affect Aging Apoptosis Behavior Binding Binding Sites Biochemistry Biological Assay Biological Models Biotin Cardiovascular Diseases Cell Nucleus Cell physiology Cells Complex Consensus Cytoplasm Cytoplasmic Granules Data Defect Development Diabetes Mellitus Disease Drosophila Proteins Drosophila genus Embryo Eukaryota Family member Female Genes Genetic Genome Goals Health Homeostasis Hour Human Image Knowledge Label Lead Link Membrane Membrane Proteins Messenger RNA Metabolism Microscopy Mission Mitochondria Mitochondrial Proteins Molecular Molecular Biology Mus Muscle National Institute of General Medical Sciences Nature Nerve Degeneration Neurons Organelles Organism Outer Mitochondrial Membrane Oxidative Stress PINK1 gene Parkin Play Post-Translational Protein Processing Process Protein Import Proteins Proteomics Public Health Quality Control RNA Binding Regulation Reporting Research Ribonucleases Ribonucleoproteins Ribosomes Role Signal Pathway Signal Transduction Starvation Sterility Stress Sucrose Testing Tissues Translating Work Yeasts age related cell type feeding fly imaging genetics in vivo mitochondrial dysfunction mutant novel oxidative damage particle protein protein interaction response sensor stress granule stressor translocase

项目摘要

PROJECT SUMMARY: Fully functional mitochondria are critically important for cells, and particularly important for tissues with high-energy demands such as muscle, neurons, and the developing embryo. As such, mitochondrial dysfunction is often associated with disease, such as neurodegeneration, cardiovascular disease and diabetes. Mitochondria work in concert with the nucleus and must import hundreds of nucleus- encoded products to supplement their own small genome. We have developed Drosophila as a model system to study mitochondria and our long-term goal is to understand the molecular mechanisms that control mitochondrial function during tissue homeostasis and development. We have found the Drosophila protein Clueless (Clu) is required to support mitochondrial function. Clu is highly conserved from yeast to human and Clu family members are ribonucleoproteins that preferentially bind nucleus-encoded mRNAs destined for mitochondria. Clu forms dynamic, large, mitochondria-associated particles in the cytoplasm. Our broad objectives for this proposal are to determine how particles form and what role they play in supporting mitochondrial function and protein import. Drosophila clu mutants are sick and sterile with damaged mitochondria. Clu associates with proteins located in the mitochondrial outer membrane, including the translocase responsible for protein import. Clu also associates with the ribosome at the outer membrane. We hypothesize that Clu particle formation is important for regulating mRNA localization and protein import. To test this hypothesis, our first Aim defines Clu particle dynamics and the signals that regulates it using microscopy, genetics and molecular biology. Our second Aim examines how Clu particles contribute to mRNA regulation using microscopy, molecular biology and biochemistry. Our third Aim uses molecular biology, biochemistry and genetics to examine how Clu particles regulate mitochondrial protein levels. The knowledge we expect to gain from this proposal on Clu particle regulation will be a transformative step forward because so little is known about the ribonucleoproteins involved in mitochondrial protein import, and Clu particles represent an undefined, novel cytoplasmic particle critical for mitochondrial function. Knowledge gained from the research proposed here will significantly advance our understanding of how mitochondria-localized mRNAs are regulated, translated and imported, which is a basic, fundamental process important for mitochondrial function in all cells.

项目摘要：功能齐全的线粒体对于细胞至关重要，尤其是对于具有高能需求的组织，例如肌肉，神经元和发育中的胚胎。作为这样的线粒体功能障碍通常与疾病有关，例如神经变性，心血管疾病和糖尿病。线粒体与细胞核协同工作，必须进口数百个核 - 编码产品以补充自己的小基因组。我们已经开发了果蝇作为模型系统研究线粒体和我们的长期目标是了解控制的分子机制组织稳态和发育过程中的线粒体功能。我们发现果蝇蛋白需要Clueless（CLU）以支持线粒体功能。 Clu从酵母到人类高度保守， Clu家族成员是核糖核蛋白，优先结合核编码的mRNA 线粒体。 CLU形成动态，大，线粒体相关的颗粒。我们的广阔该建议的目标是确定粒子的形成方式以及它们在支持中的作用线粒体功能和蛋白质导入。果蝇Clu突变体病态和无菌，损坏线粒体。 CLU与位于线粒体外膜的蛋白质相关，包括负责蛋白质进口的易位酶。 Clu还与外膜的核糖体相关联。我们假设Clu颗粒形成对于调节mRNA定位和蛋白质进口很重要。为了检验这一假设，我们的第一个目标定义了Clu粒子动力学和使用它调节的信号显微镜，遗传学和分子生物学。我们的第二个目标研究了CLU颗粒如何促进mRNA 使用显微镜，分子生物学和生物化学调节。我们的第三个目标使用分子生物学，生物化学和遗传学检查CLU颗粒如何调节线粒体蛋白水平。知识我们期望从有关CLU粒子调节的这一建议中获利将是向前迈出的变革一步，因为关于参与线粒体蛋白进口的核糖核蛋白和CLU颗粒知之甚少代表不确定的新型细胞质颗粒对于线粒体功能至关重要。从中获得的知识这里提出的研究将大大提高我们对线粒体如何定位的理解 mRNA受到监管，翻译和进口，这是一个基本的，基本的过程，对所有细胞中的线粒体功能。