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

• 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
• 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

 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。真核细胞具有用于损伤预防和响应的多层系统。在人类和各种模型系统中的许多研究都涉及线粒体蛋白质降解作为第一道防线之一。我们已经发现了一个以进化上保守的Vms1蛋白为中心的系统，该系统以应激反应的方式促进蛋白质从线粒体外膜的去除。我们提出了一个雄心勃勃的跨学科计划来描述这种蛋白质及其相关蛋白在线粒体质量控制中的调节和功能。首先，我们提出 确定的结构和生化基础的压力响应本地化的Vms1线粒体。这涉及抑制性分子内相互作用和Vms1与修饰的鞘脂的相互作用。其次，我们建议确定Vms1本地化的应激反应的机制，最初的重点是在压力下迁移到线粒体的脂质修饰酶。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是有效的。最后，我们将使用细胞培养和小鼠模型的组合来确定Vms1在哺乳动物中的生化和生理功能。这包括鉴定降解底物以及定义缺乏Vms1的小鼠的表型。