Investigating the molecular mechanism and function of mitochondrial tethering

项目摘要 我们感兴趣的是线粒体在细胞内的分布和细胞之间的动态相互作用 功能。线粒体不仅对细胞的能量生产很重要，而且在细胞周期中也起着关键作用 进展、分化、免疫反应、脂质和钙稳态，以及细胞凋亡。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，这并不令人惊讶。 线粒体结构异常与越来越多的疾病有关。这很好 认识到线粒体的分裂、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，积极地将细胞器拴在特定的细胞位置和 结构，包括其他细胞器，正变得越来越明显。虽然拴系在以下方面起着关键作用 线粒体的定位，细胞器间的接触，因此，细胞中的功能，从酵母到 神经元、分子机制和调控机制还知之甚少。在这笔赠款的目标中，我们将 通过使用酵母中线粒体-内质网-皮质系绳作为模型来解决这一缺陷，以了解其机制 以及对线粒体链和它们创建的多功能线粒体膜接触部位的调节。 拟议的工作将解决线粒体拴系对细胞产生的令人兴奋和意想不到的影响。 组织和职能。这些目标是为了揭示线粒体拴系物用于 定位线粒体，形成细胞器间的接触，并阐明其功能和生理 这些活动的后果。通过这样做，这项工作将为新的治疗策略提供洞察力 一种人类疾病的情况，在这种情况下，位置的操纵和接触由 线粒体可以用来积极地影响细胞健康和动态平衡。

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.