Coordinated Regulation of Mitochondrial Surveillance

线粒体监视的协调调节

• 批准号: 10475354
• 负责人: Natasha Kirienko
• 金额: $ 5.64万
• 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/10475354
• 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（及其自我损害的倾向） 活性氧损害）线粒体是稳态监视的重要目标 途径。线粒体功能障碍和监视缺陷越来越多地与人类健康问题有关， 包括代谢，神经系统和心血管疾病，癌症甚至衰老。最近的发现 证明存在几种不同的程序来监视线粒体功能和健康，包括 线粒体展开的蛋白质反应（UPRMT），乙醇和应力反应元件（ESRE）监视 途径以及线粒体材料的自噬降解。最近的发现表明 线粒体应力触发双齿分辨率机制，其中伴侣和其他的表达 压力缓解因素被上调，而一般细胞翻译受到抑制，以恢复 在线粒体周转之前必须进行体内平衡。该研究计划的目的是获得 可以更好地理解这些途径，无论是单独的还是相互互动。另外，他们 与核心细胞机械的相互作用（例如蛋白质翻译）也特别感兴趣，尤其是 与解决线粒体应力的范式有关。我们的第一个目标结合了遗传和 生化方法，以识别ESRE途径用于介导适应性应力反应的机制。 我们对ESRE网络功能的基本机制的理解存在关键差距，例如 结合ESRE核苷酸基序元件的转录因子的身份，该途径如何激活， 以及它如何促进对线粒体损伤的抵抗力。我们的第二个目标是研究一种新型的核糖体蛋白 修改，这是ESRE响应的关键方面，并塑造了对线粒体损伤的响应。我们的 分析将确定激活此修饰的条件，是否可以逆转，其在 控制蛋白质翻译及其与线粒体监测的关系。要回答这些问题，我们 将使用基于CRISPR的遗传学，体外生化和定量质谱法。第三，a 更广泛的目标侧重于ESRE，UPRMT，其他线粒体监视网络和 线粒体。例如，我们将探索触发这些监视程序中的每一个并阐明的事件 这些途径的相互作用和相互依赖性。我们有兴趣确定细胞是否激活 这些途径以自主方式，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。我们对导致激活线粒体周转的事件特别感兴趣 （即线粒体），因为它代表了对深刻细胞变化的不可逆转的承诺。我们将使用 研究这些事件的生化，遗传和细胞生物学方法。