Mitochondrial Fidelity and Homeostasis

项目摘要/摘要 拟议的研究计划的总体愿景是确定进化如何保守 线粒体质量控制模块的功能是维持细胞的存活，以及这些功能是如何实现的 被操控以获得临床益处。哈利蒙丘克实验室的研究重点是提供更好的 了解影响线粒体生物发生、功能和完整性的多层次过程。这个 总体目标包括：1)对相关因素进行彻底的分子表征；2)剖析它们的作用 和在相关生物机制中的协调行动；以及3)调查相关的调控和 信号事件及其潜在的治疗相关性。为此，米拉的这项提议侧重于一个群体 调节线粒体保真度和保持正常线粒体功能的基本机制 在细胞/有机体的整个生命周期中。线粒体及其复合蛋白的稳态(蛋白稳态) 网络涉及多个动态过程和路径，以适应动态平衡挑战和变化 随着时间的推移。这些机制的多方面生物学作用与正常细胞高度相关 生理学和目前尚无有效治疗方法的一系列人类疾病。渐进式 线粒体衰竭已成为常见退行性疾病的主要致病因素，如 青光眼，听力损失，帕金森氏症，肌萎缩侧索硬化症，各种神经病，痴呆， 心血管疾病和某些癌症。尽管有很多研究，但这些疾病的分子病因学 其病理机制仍不清楚。因此，对线粒体的调节机制有了更好的理解 保真度、功能和完整性，以及这些机制的失败如何导致上述临床表现，是 具有核心重要性。统一于线粒体保真度和蛋白质动态平衡的首要主题，这 研究计划试图研究：1)蛋白质降解控制/调节蛋白质稳定性的机制， 线粒体膜内的丰富、组装和修复；2)一种微妙的蛋白质 线粒体基质中的动态平衡得以建立和维持。在每一种情况下，拟议的工作都将 专注于一组专门的多功能因子，它们介导线粒体自我保护，并高度 与人类健康相关。目标是解决有关键的功能角色的悬而未决的问题 分子因子利用两个备受赞誉的互补模型，酿酒酵母和培养 人类细胞。这项研究将揭示监管、动态整合和协调的新机制 对线粒体亚蛋白质组适应动态平衡和 生理需求和挑战。该项目的成功成果将提供前所未有的 对线粒体新陈代谢、生物能量学、蛋白质平衡和挑战的协调的见解 关于年龄相关性疾病发病机制的最新观点。它们还可以帮助开发新的 针对随着年龄增长而发生的退行性疾病和相关病理的治疗/预防策略。

PROJECT SUMMARY/ABSTRACT The overall vision of the proposed research program is to determine how evolutionary conserved mitochondrial quality control modules function to maintain cell survival, and how these functions can be manipulated to achieve clinical benefits. Research in the Khalimonchuk lab is focused on providing a better understanding of multilayered processes that mediate mitochondrial biogenesis, function and integrity. The general goals include: 1) thorough molecular characterization of factors involved; 2) dissection of their roles and concerted action in relevant biological mechanisms; and 3) investigation of associated regulatory and signaling events and their potential therapeutic relevance. To that end, this MIRA proposal focuses on a group of fundamental mechanisms that mediate mitochondrial fidelity and preserve normal mitochondrial functions throughout a lifecycle of a cell/organism. The mitochondria and its complex protein homeostasis (proteostasis) network involve multiple dynamic processes and pathways that adapt to homeostatic challenges and change over time. The multifaceted biological roles of these mechanisms are highly relevant to both normal cellular physiology and a wide range of human disorders for which no effective therapies presently exist. Progressive mitochondrial failure has emerged as a central causative factor of prevalent degenerative diseases such as glaucoma, hearing loss, Parkinsonism, amyotrophic lateral sclerosis, various neuropathies, dementia, cardiovascular disorders, and certain cancers. In spite of much research, the molecular etiology of these pathologies remains obscure. Thus, a greater understanding of the mechanisms that mediate mitochondrial fidelity, function, and integrity, and how failure of these mechanisms drives the above clinical manifestations, is of central importance. Unified by an overarching topic of mitochondrial fidelity and protein homeostasis, this research program seeks to study: 1) the mechanisms that proteolytically control/regulate protein stability, abundance, assembly, and repair within the inner mitochondrial membrane and 2) how a delicate protein homeostasis in the mitochondrial matrix is established and maintained. In each case, the proposed work will focus on a group of dedicated versatile factors that mediate mitochondrial self-preservation and are highly relevant to human health. The goal is to address unresolved questions concerning the functional roles of key molecular factors using two lauded complementary models, the yeast Saccharomyces cerevisiae and cultured human cells. The research will uncover novel mechanisms of regulation, dynamic integration, and concerted spatiotemporal action that are critical for mitochondrial sub-proteomes to adjust to homeostatic insults and physiological demands and challenges. Successful outcomes from this project will provide unprecedented insights into the coordination of mitochondrial metabolism, bioenergetics, and proteostasis and challenge current views on mechanisms of age-associated maladies. They may also aid in the development of new treatment/prophylaxis strategies against degenerative diseases and related pathologies that occur with age.