A control center for mitochondrial navigation in neurons

神经元线粒体导航的控制中心

• 批准号: 10276624
• 负责人: XINNAN WANG
• 金额: $ 35.43万
• 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/10276624
• 关键词: Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Binding; Biological; Calcium; Cells; Cellular biology; Complex; Data; Defect; Disease; Drosophila genus; Economics; Environment; Eukaryotic Cell; Genetic; Glucose; Health; Homeostasis; Hypoxia; In Vitro; Inner mitochondrial membrane; Intervention; Kinesin; Limb structure; Link; Membrane; Mission; Mitochondria; Movement; Nature; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurons; Nutrient; PINK1 gene; Parkinson Disease; Pathway interactions; Peripheral Nervous System Diseases; Phosphorylation; Proteins; Public Health; Role; Signal Transduction; Stimulus; Stress; Ubiquitination; United States National Institutes of Health; Validation; Work; cell motility; experimental study; in vivo; mitochondrial membrane; multicatalytic endopeptidase complex; novel; parkin gene/protein; protein complex; response; tool

We seek 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 these discrete Miro-pathways functionally coordinate or converge on mitochondrial integrity in response to various stimuli and stresses? In this proposal, we will probe 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.

我们试图了解控制线粒体运动的调节机制 在细胞中。包括米尔顿、Miro和驱动蛋白-1重链（KHC）的蛋白质复合物， 对神经元中的线粒体运输至关重要。米罗位于中央枢纽，允许多个 控制线粒体运动的细胞信号。这些信号包括线粒体自噬，钙， 缺氧和营养物质的可利用性等。此外，与本提案最相关的是，我们有 获得了令人兴奋的初步结果表明，一种新的机械跨越两个 线粒体外膜和内膜-线粒体膜间隙桥接 (MIB)复合物，稳定米罗和调节线粒体运动。这一新发现和我们的 过去的工作在基础细胞生物学的交叉点提出了一个紧迫的问题， 神经生物学：这些离散的Miro通路如何在功能上协调或汇聚 线粒体完整性对各种刺激和压力的反应？在本提案中，我们将探讨 这些问题使用经典的细胞生物学和神经生物学方法， 功能验证的强大遗传工具（果蝇）。目的1：解剖功能性 MIB-Miro复合物的重要性。目的2：确定Miro相互作用的性质 与其合作伙伴的关系。目的3：探索调控信号的相互作用， 米罗的机器