Investigating the molecular mechanism and function of mitochondrial tethering

研究线粒体束缚的分子机制和功能

• 批准号: 10579930
• 负责人: Laura L Lackner
• 金额: $ 32.14万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579930
• 关键词: Address; Affect; Aging; Apoptotic; Architecture; Binding Proteins; Biochemical; Biological; Calcium; Cell Cycle Progression; Cell Death; Cell membrane; Cell physiology; Cells; Cellular biology; Communication; Complex; Core Protein; Couples; Coupling; Cues; Data; Development; Disease; Dissection; Dynein ATPase; EF Hand Motifs; Environment; Genes; Goals; Grant; Health; Homeostasis; Immune response; Individual; Link; Lipids; Membrane; Mitochondria; Mitochondrial Inheritance; Modeling; Molecular; Nature; Neurons; Nuclear; Organelles; Pathway interactions; Physiological; Play; Positioning Attribute; Production; Proteins; Publishing; Regulation; Role; Shapes; Site; Structure; System; Techniques; Testing; Time; Visualization; Work; Yeasts; cell motility; combinatorial; fitness; human disease; insight; integration site; interdisciplinary approach; interest; mitochondrial membrane; mutant; novel; novel therapeutic intervention; screening; spatiotemporal; tool

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.

项目概要 我们对线粒体的细胞内分布和细胞内的动态相互作用感兴趣 功能。线粒体不仅对细胞能量产生很重要，而且在细胞周期中也发挥着关键作用 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，这并不奇怪 异常的线粒体结构与越来越多的疾病有关。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，主动将细胞器束缚到特定细胞位点的关键贡献和 结构，包括其他细胞器，变得越来越明显。虽然网络共享在其中起着至关重要的作用 线粒体定位、细胞器间接触，以及因此从酵母到细胞的细胞功能 对于神经元的分子机制和调节知之甚少。为了实现这笔赠款的目标，我们将 通过使用酵母中的线粒体-内质网-皮层系链作为模型来理解这一机制来解决这一缺陷 以及线粒体系绳及其产生的多功能线粒体膜接触位点的调节。 拟议的工作将解决线粒体系绳对细胞的令人兴奋和意想不到的影响 组织和职能。目标是揭示线粒体系绳所使用的基本机制 定位线粒体并形成细胞器间接触并阐明功能和生理学 这些活动的后果。在此过程中，这项工作将为新的治疗策略提供见解。 一系列人类疾病，其中位置和接触的操纵 线粒体可用于积极影响细胞健康和体内平衡。