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：
9097775
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/9097775
关键词：
Apoptosis Binding Biochemical Biochemical Genetics Biochemistry Biological Biological Models Cell Culture Techniques Cells Cellular biology Chronic Disease Complex Cultured Cells Data Defect Deterioration Enzymes Eukaryotic Cell Excision Functional disorder Genetic Health Heart Human 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 Mus Mutagenesis N-terminal Outer Mitochondrial Membrane Pathologic Phenotype Physiological Prevention Protein Family Proteins Proteomics Quality Control Recruitment Activity Regulation Respiration Role Sphingolipids Stress Structure System Testing Tissues Yeasts base genetic approach hemodynamics human disease interdisciplinary approach mouse model novel programs protein degradation protein function receptor research study 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（由申请人提供）：进行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。许多人类研究和各种模型系统都涉及线粒体蛋白。我们发现了一种以进化上保守的 Vms1 蛋白为中心的系统，它可以以应激反应的方式促进线粒体外膜上的蛋白质去除。雄心勃勃的跨学科计划来描述这种蛋白质及其相关物在线粒体质量控制中的调节和功能。确定 Vms1 应激反应定位到线粒体的结构和生化基础，这涉及抑制性分子内相互作用以及 Vms1 与修饰的鞘脂的相互作用。其次，我们建议确定 Vms1 应激反应性的机制。我们还将证实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，我们将结合细胞培养和小鼠模型来确定 Vms1 在哺乳动物中的生化和生理功能，这包括鉴定降解的底物以及定义缺乏 Vms1 的小鼠的表型。