A control center for mitochondrial navigation in neurons

神经元线粒体导航的控制中心

• 批准号: 10643833
• 负责人: XINNAN WANG
• 金额: $ 36.13万
• 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/10643833
• 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; Maps; Membrane; Mission; Mitochondria; Movement; Nature; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurons; Nutrient availability; PINK1 gene; Parkin; Parkinson Disease; Pathway interactions; Peripheral Nervous System Diseases; Persons; 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; 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Milton，Miro和Kinesin-1重链（KHC）在内的蛋白质复合物为 神经元中线粒体转运必不可少的。中央集线器的Miro Residences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，钙， 另外，缺氧和营养物的可用性等。此外，与该提议最相关的是，我们有 获得了令人兴奋的初步结果，表明一种新型机械跨越了 线粒体外膜和内膜 - 线粒体膜间空间桥接 （MIB）复合物，稳定Miro并调节线粒体运动。这个新发现和我们的 过去的工作在基本细胞生物学和 神经生物学：这些离散的Miro-Pathways如何在功能上坐标或收敛 线粒体完整性响应各种刺激和应力？在此提案中，我们将证明 这些问题使用经典细胞生物学和神经生物学方法结合了 功能验证的强大遗传工具（果蝇）。目标1：剖析功能 MIB-MIRO复合物的意义。目标2：确定米罗相互作用的性质 及其约束伙伴。目标3：探索监管信号的相互作用和 米罗的机械。