A control center for mitochondrial navigation in neurons

来自家长资助的项目摘要1R01GM143258 我们试图了解控制线粒体运动的调节机制。 在牢房里。一种包括米尔顿、米罗和运动蛋白-1重链(KHC)的蛋白质复合体 对神经元中的线粒体运输是必不可少的。Miro驻留在中央枢纽，允许多个 控制线粒体运动的细胞信号。这些信号包括有丝分裂，钙， 低氧和营养可获得性等。此外，与这项提议最相关的是，我们有 获得了令人兴奋的初步结果，表明一种新的机械跨越了 线粒体外膜和内膜--线粒体膜间间隙桥接 (MIB)复合体，稳定MIRO并调节线粒体运动。这一新发现和我们的 过去的工作在基础细胞生物学和细胞生物学的交叉点上提出了一个紧迫的问题 神经生物学：这些离散的微通路如何在功能上协调或汇聚 线粒体在应对各种刺激和压力时的完整性？在这项提案中，我们将 用经典的细胞生物学和神经生物学相结合的方法探索这些问题 利用强大的遗传工具(果蝇)进行功能验证。目标1：剖析功能 MIB-Miro复合体的意义。目标2：确定Miro与其相互作用的性质 有约束力的伙伴。目的3：探讨调控信号和机制之间的相互作用。 米罗。

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.