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A control center for mitochondrial navigation in neurons

神经元线粒体导航的控制中心

基本信息

批准号：
10799224
负责人：
XINNAN WANG
金额：
$ 4.97万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

Project Summary from Parent Grant 1R01GM143258 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.

来自母基金1 R 01 GM 143258的项目摘要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。Miro位于中央集线器，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，我们将结合经典的细胞生物学和神经生物学方法来探索这些问题利用强大的遗传工具（果蝇）进行功能验证。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，有约束力的伙伴目的3：探索调节信号和机制的相互作用，米罗