Admin Supp: Investigating the molecular mechanism of mitochondrial tethering

项目摘要 我们感兴趣的是线粒体的细胞内分布和细胞内的动态相互作用， 功能线粒体不仅在细胞能量产生中起重要作用，而且在细胞周期中起关键作用 进展、分化、免疫应答、脂质和钙稳态以及凋亡性细胞死亡。这些 不同的作用与线粒体的形状和细胞位置密切相关。因此， 异常的线粒体结构与越来越多的疾病有关。公 我认识到，线粒体分裂，融合和运动都有助于线粒体的整体分布 在一个细胞内。然而，积极地将细胞器拴系到特定的细胞位点和 结构，包括其他细胞器，正变得越来越明显。虽然网络共享在 线粒体定位，细胞器间的接触，并因此，从酵母细胞的细胞功能， 神经元，分子机制和调节知之甚少。为了实现这一目标，我们将 通过使用酵母中的神经元-ER-皮质系链作为模型来理解机制， 以及线粒体系链和它们所产生的多功能线粒体膜接触位点的调节。 这项拟议的工作将解决线粒体系链对细胞的令人兴奋和意想不到的影响。 组织和功能。其目标是揭示线粒体系链的基本机制， 定位线粒体，形成细胞器间的接触，并阐明功能和生理 这些活动的后果。在这样做的过程中，这项工作将提供深入了解新的治疗策略， 一系列人类疾病状况，其中位置的操纵和由 线粒体可用于积极影响细胞健康和体内平衡。所要求的补充是 购买MSM 400解剖显微镜。该系统对于支持直接 影响和解决为该项目提出的目标。通过购买MSM 400解剖显微镜， 必要的，但很快将是非功能性的四分体解剖显微镜将被取代，新的技术直接 与项目相关的是可行的。

Project Summary We are interested in the dynamic interplay between the intracellular distribution of mitochondria and cellular function. Mitochondria are important not only for cellular energy production but also play critical roles in cell cycle progression, differentiation, immune responses, lipid and calcium homeostasis, and apoptotic cell death. These diverse roles are intimately connected to mitochondrial shape and cellular position. Thus, it is not surprising aberrant mitochondrial architecture has been implicated in an ever-increasing number of diseases. It is well appreciated that mitochondrial division, fusion, and motility all contribute to the overall distribution of mitochondria within a cell. However, the critical contributions of actively tethering the organelle to specific cellular sites and structures, including other organelles, are becoming increasingly evident. While tethering plays a critical role in mitochondrial positioning, interorganelle contact, and, consequently, cellular function in cells from yeast to neurons, the molecular mechanisms and regulation are poorly understood. In the aims of this grant, we will address this deficit by using a mitochondria-ER-cortex tether in yeast as a model to understand the mechanism and regulation of mitochondrial tethers and the multifunctional mitochondrial membrane contact sites they create. The proposed work will address the exciting and unexpected impacts mitochondrial tethers have on cellular organization and function. The goals are to uncover fundamental mechanisms used by mitochondrial tethers to position mitochondria and form interorganelle contacts and elucidate the functional and physiological consequences of these activities. In doing so, this work will provide insight into novel therapeutic strategies for a range of human disease conditions in which the manipulation of the position and the contacts made by mitochondria can be used to positively influence cellular health and homeostasis. The requested supplement is for the purchase of an MSM 400 Dissecting Microscope. The system is critical to support experiments that directly impact and address the goals put forth for this project. By acquiring the MSM 400 Dissecting Microscope, an essential but soon to be non-functional tetrad dissection microscope will be replaced and new techniques directly relevant to the project will be feasible.