The role and regulation of mitochondrial localization in mature neurons.

项目总结/摘要 线粒体定位的动态调节对于各种能量需求和稳态是至关重要的 亚细胞区域的维持。控制线粒体运动、动力学、锚定和 质量控制已经确定。然而，人们对神经元的信号传导机制知之甚少。 协调线粒体定位在短期和长期的环境和生理反应 刺激。线粒体定位的这种适当调节在具有独特和独特的神经元中特别重要。 导致线粒体生物合成之间不匹配的基本问题的细长结构 线粒体的功能主要集中在两个部位（细胞体）和对线粒体功能要求较高的部位（轴突和突触）。越来越多的证据 表明轴突和突触的不规则线粒体定位与许多 神经系统疾病，包括阿尔茨海默病，神经变性和再生失败。这 一项提案旨在阐明神经元如何在两种基本条件下调节线粒体定位 包括年龄和伤病。此外，我们建议确定如何调节线粒体定位 影响神经元功能的维持以抵抗损伤和老化。这一建议是建立在最近在 体内研究表明，成年神经元经历逐渐减少的线粒体运动。我们的实验室和其他 也揭示了受损的神经元会剧烈改变线粒体的运动和定位， 轴突再生能力。神经元调节线粒体定位的潜在机制 对衰老和损伤的情况仍然知之甚少。缺乏这方面的知识阻碍了发展 神经系统疾病的治疗策略，如阿尔茨海默病和神经损伤， 与异常的线粒体定位有关。我们联合收割机将秀丽隐杆线虫的遗传学， 线粒体生物学、创新的体内成像和激光轴突切断术来解决这些未满足的需求。我们 初步数据表明，DLK-1 MAPK信号通路，一种与突触相关的保守通路， 在阿尔茨海默病模型中，轴突再生和进行性神经退行性变可能是一种 神经元中线粒体定位的新调节剂。该提案包括三个具体目标，以回答 神经元如何在衰老和损伤条件下调节线粒体定位（目标1）， 线粒体在成年神经元损伤后的恢复中（目的2），以及线粒体之间的通讯如何 线粒体和细胞核控制DLK-1信号传导，从而线粒体功能和轴突再生 (Aim 3）。我们希望我们提出的实验将实现对机制的新理解， 通过调节衰老和受伤时的线粒体功能来维持神经系统的最佳功能 神经元此外，我们的研究结果将提供更好的见解，以新的治疗方法，以恢复神经元， 神经损伤后的功能

PROJECT SUMMARY/ABSTRACT Dynamic regulation of mitochondrial localization is vital for the various energy demands and homeostasis maintenance of subcellular regions. Key components governing mitochondrial motility, dynamics, anchoring, and quality control have been identified. However, little is known about the signaling mechanisms by which neurons coordinate mitochondrial localization in the short and long term in response to environmental and physiological stimuli. This proper regulation of mitochondrial localization is particularly important in neurons with unique and elongated structures that lead to a fundamental problem of a mismatch between the mitochondrial biosynthesis site (cell body) and the high-demanding site for mitochondrial function (axon and synapse). Growing evidence indicates that an irregular mitochondrial localization to the axon and synapse is closely associated with many neurological disorders, including Alzheimer's disease, nerve degeneration, and regeneration failure. This proposal aims to elucidate how neurons regulate mitochondrial localization in two fundamental conditions including age and injury. In addition, we propose to determine how the regulation of mitochondrial localization affects the maintenance of neuronal function against injury and aging. This proposal is built based on recent in vivo studies that adult neurons undergo progressively reduced mitochondrial movement. Our lab and others have also revealed that injured neurons acutely change mitochondrial movement and localization, determining axon regeneration ability. The underlying mechanisms by which neurons regulate mitochondrial localization in aging and injury conditions remain poorly understood. Lack of this knowledge hinders the development of therapeutic strategies for neurological diseases such as Alzheimer's disease and nerve injury that have been associated with abnormal mitochondrial localization. We combine Caenorhabditis elegans genetics, mitochondrial biology, innovative in vivo imaging, and laser axotomy to address these unmet needs. Our preliminary data suggest that the DLK-1 MAPK signaling, a conserved pathway associated with synapse development, axon regeneration, and progressive neurodegeneration in Alzheimer's disease model, could be a novel regulator of mitochondrial localization in neurons. This proposal consists of three specific aims to answer how neurons regulate mitochondrial localization in aging and injury conditions (Aim 1), what the role of mitochondria in the recovery of the adult neurons after injury (Aim 2), and how the communication between mitochondria and nucleus controls the DLK-1 signaling, thereby mitochondria function and axon regeneration (Aim 3). We expect that our proposed experiments will achieve a new understanding of the mechanisms that maintain the optimal function of the nervous system by regulating mitochondrial function in aging and injured neurons. Also, our findings will provide better insight into novel therapeutic approaches to restoring neuronal function after nerve injury.