The Functions of Mitochondrial Membrane Contact Sites in Space and Time

线粒体膜接触位点在空间和时间上的功能

基本信息

批准号：
10388822
负责人：
Jason Casler
金额：
$ 6.72万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10388822
关键词：
Address Affect Aging Binding Biochemical Biochemical Genetics Biocompatible Materials Biological Biology Cell membrane Cells Communication Complex Development Dissection Dynein ATPase Ethics Fluorescence Microscopy Genes Genetic Goals Group Meetings Health Homeostasis Human Individual Interdisciplinary Study Knowledge Learning Malignant Neoplasms Mediating Mentorship Mission Mitochondria Molecular Nerve Degeneration Nuclear Organelles Paper Physiological Play Positioning Attribute Process Proteins Public Health Regulation Research Research Personnel Respiratory physiology Role Running Saccharomyces cerevisiae Saccharomycetales Science Site Stress Stress Tests System Techniques Testing Time Training United States National Institutes of Health Work Yeasts career development chemical genetics design diversity and inclusion environmental stressor fitness genetic approach human disease interdisciplinary approach live cell imaging metabolome mitochondrial membrane novel programs research and development response screening skill acquisition skills stressor symposium tool

项目摘要

Mitochondria form elaborate reticular networks that make physiologically important contacts with nearly every other organelle. Recently, mitochondrial membrane contact sites (MMCSs) have been shown to play a role in regulating mitochondrial function. Beyond physically tethering organelles, MMCSs have been implicated in interorganelle communication, modulating mitochondrial fusion and fission, and adapting the mitochondrial network to function under stress conditions. Despite progress in defining the molecular composition of individual MMCSs, little is known about the functions of MMCSs or how they are regulated in space and time. Previous studies have focused on individual MMCSs under a narrow range of biological conditions; however, multiple MMCSs exist simultaneously, creating a dynamic network that controls the function of mitochondria. Thus, defining the functions of MMCSs and dissecting how these functions are coregulated in space and time to modulate mitochondrial function represents a well-recognized gap in knowledge. To address this complex problem, this proposal will analyze the simplified MMCS network of the budding yeast Saccharomyces cerevisiae. A multidisciplinary approach will be used to characterize novel functions of the mitochondria-ER- cortex anchor (MECA) and probe how these functions are coregulated with other MMCSs to adapt the mitochondrial network to function under various stresses. MECA forms a unique tripartite organelle contact site between mitochondria, the ER, and the plasma membrane. Work in Aim 1 will determine the mechanism and function of contact between MECA and the ER and test the hypothesis that MECA-ER contacts are involved in mitochondrial respiratory function. Work in Aim 2 will use unbiased screening approaches to identify novel genes and metabolites involved in mitochondrial functions that are regulated by MECA. Work in Aim 3 will characterize the dynamic regulation of MECA and other MMCSs in response to environmental or mitochondrial stresses and test the hypothesis that MMCSs are coregulated to adapt the mitochondrial network for optimal function. This proposal will identify novel functions of MECA and describe how this contact site and others are regulated through space and time. This work will extend beyond the characterization of a MMCS in a single context and begin dissecting how MMCSs are regulated at a systems level to modulate mitochondrial function. The training plan in this proposal is designed to teach the skills required to operate as an independent researcher. The central focus will be training in interdisciplinary research and career development skills. This proposal provides the opportunity to learn state-of-the-art biochemical, genetic, and systems level approaches to ask fundamental questions about organelle biology. Scientific communication and networking skills will be strengthened by authoring scientific papers and presenting at group meetings and conferences. This proposal also provides training in mentorship, ethical research practices, and promoting diversity and inclusion in science.

线粒体形成复杂的网状网络，与几乎所有生物都具有重要的生理联系其他细胞器。最近，线粒体膜接触位点（MMCS）已被证明在调节线粒体功能。除了物理束缚细胞器之外，MMCS 还与细胞器间通讯，调节线粒体融合和裂变，并适应线粒体网络在压力条件下发挥作用。尽管在定义个体的分子组成方面取得了进展对于 MMCS，人们对 MMCS 的功能或它们如何在空间和时间上进行调节知之甚少。以前的研究集中在狭窄的生物条件下的单个 MMCS；然而，多个 MMCS 同时存在，形成一个控制线粒体功能的动态网络。因此，定义 MMCS 的功能并剖析这些功能如何在空间和时间上共同调节调节线粒体功能代表了公认的知识空白。为了解决这个复杂的问题问题，本提案将分析芽殖酵母 Saccharomyces 的简化 MMCS 网络酿酒酵母。将采用多学科方法来表征线粒体-ER-的新功能皮层锚定（MECA）并探究这些功能如何与其他 MMCS 共同调节以适应线粒体网络在各种压力下发挥作用。 MECA形成独特的三方细胞器接触位点线粒体、内质网和质膜之间。目标 1 的工作将确定机制和 MECA 和 ER 之间的接触函数并检验 MECA-ER 接触参与的假设线粒体呼吸功能。目标 2 的工作将使用公正的筛选方法来识别新基因以及参与受 MECA 调节的线粒体功能的代谢物。目标 3 中的工作将具有以下特点： MECA 和其他 MMCS 响应环境或线粒体应激的动态调节，检验 MMCS 共同调节以使线粒体网络实现最佳功能的假设。这提案将确定 MECA 的新颖功能，并描述如何监管该联系网站和其他网站穿越空间和时间。这项工作将超越单一环境中 MMCS 的表征，开始剖析 MMCS 如何在系统水平上进行调节以调节线粒体功能。本提案中的培训计划旨在教授作为独立研究人员所需的技能。中心重点将是跨学科研究和职业发展技能的培训。这个提议提供学习最先进的生化、遗传和系统级方法来提问的机会有关细胞器生物学的基本问题。科学沟通和网络技能将通过撰写科学论文和在小组会议上发言来加强。这个提议还提供指导、道德研究实践以及促进科学多样性和包容性方面的培训。