The Functions of Mitochondrial Membrane Contact Sites in Space and Time

线粒体形成复杂的网状网络，与几乎每一个 其他细胞器。最近，线粒体膜接触位点(MMCSs)被证明在 调节线粒体功能。除了物理上的束缚细胞器，MMCS还被牵连到 细胞器间的通讯，调节线粒体的融合和分裂，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 关于MMCSs，人们对MMCSs的功能以及它们在空间和时间上是如何调节的知之甚少。上一首 研究集中在狭窄生物条件下的单个MMCS；然而，多个 MMCS同时存在，创建了一个控制线粒体功能的动态网络。因此， 定义MMCS的功能，并剖析这些功能是如何在空间和时间上协同调节的 调节线粒体功能代表了公认的知识鸿沟。为了解决这个复杂的问题 问题，这项建议将分析发芽酵母的简化MMCs网络 酿酒。将使用多学科方法来表征线粒体的新功能-内质网- 皮质锚(MECA)，并探索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形成独特的三分体细胞器接触部位 线粒体、内质网和质膜之间。目标1中的工作将决定机制和 MECA与内质网接触的作用及MECA-ER接触参与的假设检验 线粒体呼吸功能。AIM 2的工作将使用无偏见的筛选方法来识别新的基因 以及参与线粒体功能的代谢物，由MECA调节。《目标3》中的工作将描述 MECA和其他MMCSs对环境或线粒体应激的动态调节 测试MMCSs被协同调节以适应线粒体网络以实现最佳功能的假设。这 建议书将确定MECA的新功能，并描述如何监管该联系地点和其他联系地点 穿越空间和时间。这项工作将超越单一背景下对MMC的描述，并 开始剖析MMCS是如何在系统水平上调节线粒体功能的。 本提案中的培训计划旨在传授作为独立研究人员运作所需的技能。 中心重点将是跨学科研究和职业发展技能方面的培训。这项建议 提供机会学习最先进的生化、遗传和系统水平的方法，以询问 细胞器生物学的基本问题。科学的沟通和网络技能将是 通过撰写科学论文和在小组会议和会议上发言而得到加强。这项建议 还提供指导、伦理研究实践以及促进科学多样性和包容性方面的培训。

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.