An Interdisciplinary Approach to Stress-Induced Mitochondrial Quality Control

应激诱导线粒体质量控制的跨学科方法

基本信息

批准号：
9240648
负责人：
CHRISTOPHER P. HILL
金额：
$ 38.09万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240648
关键词：
Apoptosis Binding Biochemical Biochemical Genetics Biochemistry Biological Biological Models Cell Culture Techniques Cell model Cells Cellular biology Chronic Disease Complex Crystallization Cultured Cells Data Defect Deterioration Enzymes Eukaryotic Cell Excision Functional disorder Genetic Heart Human Impairment In Vitro Knockout Mice Leucine Ligands Lipase Lipid Binding Lipids Maintenance Mammalian Cell Mammals Masks Mediating Membrane Membrane Lipids Membrane Potentials Metabolic Mitochondria Mitochondrial Proteins Modeling Molecular Molecular Conformation Mus Mutagenesis N-terminal Pathologic Pharmacology Phenotype Physiological Prevention Protein Family Proteins Proteomics Quality Control Recruitment Activity Regulation Respiration Role Sphingolipids Stress Structure System Testing Tissues Yeasts base experimental study genetic approach hemodynamics human disease interdisciplinary approach mouse model novel programs protein degradation protein function public health relevance receptor response structural biology

项目摘要

DESCRIPTION (provided by applicant): Progressive mitochondrial damage and the resulting dysfunction are key contributors to many human diseases. Eukaryotic cells have a multi-layered system for damage prevention and response. Many studies in humans and a variety of model systems have implicated mitochondrial protein degradation as one of the first lines of defense. We have uncovered a system, centered on the evolutionarily conserved Vms1 protein, that promotes the removal of proteins from the mitochondrial outer membrane in a stress- responsive manner. We propose an ambitious inter-disciplinary plan to describe the regulation and function of this protein and its associates in mitochondrial quality control. First, we propose to define the structural and biochemical basis for the stress-responsive localization of Vms1 to mitochondria. This involves both an inhibitory intramolecular interaction and the interaction of Vms1 with a modified sphingolipid. Second, we propose to determine the mechanisms underlying the stress-responsiveness of Vms1 localization, with an initial focus on a lipid-modifying enzyme that migrates to mitochondria under stress. We will also confirm our preliminary data suggesting that these mechanisms are operative in mammalian cells. Finally, we will determine the biochemical and physiological function of Vms1 in mammals using a combination of cell culture and mouse models. This includes the identification of degradation substrates as well as defining the phenotype of a mouse lacking Vms1.

描述（由适用提供）：渐进性线粒体损伤和由此产生的功能障碍是许多人类疾病的关键因素。真核细胞具有多层系统，可预防损伤和反应。许多在人类和各种模型系统中的研究已经实施了线粒体蛋白降解作为第一线防御线之一。我们发现了一个以进化构成的VMS蛋白为中心的系统，该系统以应力响应方式促进了从线粒体外膜中去除蛋白质。我们提出了一个雄心勃勃的跨学科计划，以描述该蛋白质及其在线粒体质量控制中的调节和功能。首先，我们建议为了定义VMS1对线粒体的应力响应定位的结构和生化基础。这涉及分子内相互作用和VMS1与修饰的鞘脂的相互作用。其次，我们建议确定VMS1定位的应力反应性的基础机制，最初的重点是在应激下迁移到线粒体的脂质改良酶。我们还将确认我们的初步数据表明这些机制在哺乳动物细胞中起作用。最后，我们将使用细胞培养和小鼠模型的组合来确定哺乳动物中VMS1的生化和物理功能。这包括鉴定降解底物以及定义缺乏VMS1的小鼠的表型。