Coordinated Regulation of Mitochondrial Surveillance

线粒体监视的协调调节

• 批准号: 10240482
• 负责人: Natasha Kirienko
• 金额: $ 38.46万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240482
• 关键词: Aging; Alcohol consumption; Binding; Biochemical; Biochemical Genetics; Biochemistry; Biological; Cardiovascular Diseases; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Defect; Elements; Event; Gene Expression; Genetic; Goals; Health; Homeostasis; Human; In Vitro; Link; Longevity; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Diseases; Methods; Mitochondria; Modification; Molecular Chaperones; Monitor; Nucleotides; Organism; Pathway interactions; Play; Post-Translational Protein Processing; Process; Proteins; Reactive Oxygen Species; Regulation; Research; Resistance; Resolution; Response Elements; Ribosomal Proteins; Role; Shapes; Signal Transduction; Stress; Surveillance Program; Tissues; Translations; alcohol response; base; biological adaptation to stress; cell type; interest; mitochondrial dysfunction; nervous system disorder; novel; programs; response; surveillance network; transcription factor

Summary: Due to their central role in a variety of metabolic functions (and their propensity for self-inflicted damage from reactive oxygen species) mitochondria are an important target for homeostatic surveillance pathways. Mitochondrial dysfunction and surveillance defects are increasingly linked to human health problems, including metabolic, neurological, and cardiovascular diseases, cancer, and even aging. Recent discoveries have demonstrated that several different programs exist for monitoring mitochondrial function and health, including the mitochondrial unfolded protein response (UPRmt), the ethanol and stress response element (ESRE) surveillance pathway, and the autophagic degradation of mitochondrial material. Recent discoveries have suggested that mitochondrial stress triggers a bidentate resolution mechanism, wherein the expression of chaperones and other stress-mitigating factors are upregulated while general cell translation is dampened in an effort to restore homeostasis before mitochondrial turnover becomes necessary.The goal of this research program is to gain a better understanding of these pathways, both alone and in interaction with each other. In addition, their interactions with core cellular machinery, such as protein translation, are also of particular interest, especially as it relates to the paradigm of resolving mitochondrial stress. Our first goal uses a combination of genetic and biochemical methods to identify the mechanisms used by the ESRE pathway to mediate adaptive stress responses. There are critical gaps in our understanding of the fundamental mechanisms of ESRE network function, such as the identity of the transcription factors that bind the ESRE nucleotide motif element, how this pathway is activated, and how it promotes resistance to mitochondrial damage. Our second goal is to study a novel ribosomal protein modification, which is a key aspect of the ESRE response, and shapes the response to mitochondrial damage. Our analysis will determine the conditions that activate this modification, whether it can be reversed, the role it plays in controlling protein translation, and its relationships with mitochondrial surveillance. To answer these questions, we will use CRISPR-based genetics, in vitro biochemical, and quantitative mass spectrometry approaches. Third, a broader goal focuses on the relationships between ESRE, the UPRmt, other mitochondrial surveillance networks and mitophagy. For example, we will explore the events that trigger each of these surveillance programs and elucidate the interactions and interdependence of these pathways. We are interested in determining whether cells activate these pathways in an autonomous fashion, or whether signals from one tissue can activate defense networks in other cell types. We are particularly interested in the events leading up to activation of mitochondrial turnover (i.e., mitophagy), since it represents an irreversible commitment to profound cellular changes. We will use biochemical, genetic, and cell biological approaches to study these events.

摘要：由于它们在各种代谢功能中的核心作用（以及它们自我造成的倾向）， 活性氧损伤）线粒体是体内平衡监视的重要目标 途径。线粒体功能障碍和监测缺陷越来越多地与人类健康问题联系在一起， 包括代谢、神经和心血管疾病、癌症，甚至衰老。最近的发现 表明存在几种不同的程序来监测线粒体功能和健康，包括 线粒体未折叠蛋白反应（UPRmt）、乙醇和应激反应元件（ESRE）监测 途径，以及线粒体物质的自噬降解。最近的发现表明， 线粒体应激触发了双齿分解机制，其中伴侣蛋白和其他蛋白的表达被抑制。 压力缓解因子上调，而一般细胞翻译受到抑制，以恢复 在线粒体转换成为必要之前的稳态。这项研究计划的目标是获得一个 更好地理解这些途径，无论是单独的还是相互作用的。另外他们 与核心细胞机制的相互作用，如蛋白质翻译，也是特别感兴趣的，特别是因为它 与解决线粒体压力的范例有关。我们的第一个目标是结合基因和 生物化学方法来鉴定ESRE途径介导适应性应激反应的机制。 在我们对ESRE网络功能的基本机制的理解方面存在重大差距，例如 结合ESRE核苷酸基序元件的转录因子的身份，该途径如何被激活， 以及它如何增强对线粒体损伤的抵抗力。我们的第二个目标是研究一种新的核糖体蛋白 修饰，这是ESRE反应的关键方面，并形成对线粒体损伤的反应。我们 分析将确定激活这种修改的条件，它是否可以逆转，它在其中扮演的角色， 控制蛋白质翻译，以及它与线粒体监视的关系。为了回答这些问题，我们 将使用基于CRISPR的遗传学，体外生化和定量质谱方法。三是 更广泛的目标集中在ESRE，UPRmt，其他线粒体监测网络和 线粒体自噬例如，我们将探讨触发这些监视程序的事件，并阐明 这些途径的相互作用和相互依赖。我们感兴趣的是， 这些途径以自主的方式，或者来自一个组织的信号是否可以激活防御网络， 其他细胞类型。我们特别感兴趣的事件导致激活线粒体营业额 (i.e.,线粒体自噬），因为它代表了对深刻的细胞变化的不可逆转的承诺。我们将使用 生物化学、遗传学和细胞生物学方法来研究这些事件。