A control center for mitochondrial navigation in neurons

神经元线粒体导航的控制中心

• 批准号: 10676692
• 负责人: XINNAN WANG
• 金额: $ 5.13万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676692
• 关键词: Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Binding; Biological; Calcium; Cells; Cellular biology; Complex; Disease; Drosophila genus; Economics; Genetic; Hypoxia; Inner mitochondrial membrane; Kinesin; Mission; Mitochondria; Movement; Nature; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurons; Nutrient; Parkinson Disease; Pathway interactions; Persons; Public Health; Signal Transduction; Stimulus; Stress; Therapeutic Intervention; United States National Institutes of Health; Validation; Work; cell motility; new therapeutic target; novel; protein complex; response; tool

We are seeking to understand the regulatory mechanisms that control the movements of mitochondria in cells. A protein complex that includes milton, Miro, and the kinesin-1 heavy chain (KHC) is essential for mitochondrial transport in neurons. Miro resides at the central hub to allow multiple cellular signals to control mitochondrial motility. These signals include mitophagy, calcium, hypoxia, and nutrient availability etc. Additionally, and most relevant to this proposal, we have obtained exciting preliminary results demonstrating that a novel machinery spanning both the mitochondrial outer and inner membranes–the mitochondrial intermembrane space bridging (MIB) complex, stabilizes Miro and regulates mitochondrial motility. This new discovery and our past work raise a burning question at the intersection of fundamental cell biology and neurobiology: How do these discrete Miro-pathways functionally coordinate or converge on mitochondrial integrity in response to various stimuli and stresses? In this project we are probing these questions using classical cell biological and neurobiological approaches combined with a powerful genetic tool (fruit flies) for functional validation. Aim 1: To dissect the functional significance of the MIB-Miro complex. Aim 2: To determine the nature of Miro interaction with its binding partners. Aim 3: To explore the interplay of the regulatory signals and machineries of Miro.

我们正在寻求了解控制运动的调节机制， 细胞中的线粒体。一种蛋白质复合物，包括米尔顿、Miro和驱动蛋白-1重链 链（KHC）对于神经元中的线粒体运输是必需的。米罗位于中央枢纽， 允许多种细胞信号控制线粒体运动。这些信号包括 线粒体自噬、钙、缺氧和营养素可用性等。此外，与 这个建议，我们已经获得了令人兴奋的初步结果表明，一种新的 跨越线粒体外膜和内膜的机器-线粒体 膜间隙桥接（MIB）复合物，稳定Miro并调节线粒体 能动性这一新发现和我们过去的工作在交叉点上提出了一个紧迫的问题 基础细胞生物学和神经生物学：这些离散的微通路 在功能上协调或汇聚线粒体完整性以响应各种刺激 和压力吗在这个项目中，我们正在使用经典细胞生物学和 神经生物学方法与功能强大的遗传工具（果蝇）相结合， 验证。目的1：探讨MIB-Miro复合体的功能意义。目标二： 确定Miro与其结合伴侣相互作用的性质。目标3：探索 米罗的调节信号和机制的相互作用。