The role and regulation of mitochondrial localization in mature neurons.

成熟神经元线粒体定位的作用和调节。

• 批准号: 10634116
• 负责人: SUNG MIN HAN
• 金额: $ 37.71万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634116
• 关键词: Acute; Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Anabolism; Animals; Axon; Axotomy; Biology; Caenorhabditis elegans; Cell Nucleus; Cells; Communication; Data; Defect; Development; Distal; Failure; Genetic; Genetic Models; Goals; Homeostasis; Homologous Gene; Imaging Techniques; Injury; Knowledge; Lasers; MAPK1 gene; Maintenance; Mediating; Mediator; Mitochondria; Molecular; Monitor; Movement; Mutation; Natural regeneration; Nerve Degeneration; Nervous System Physiology; Neuronal Injury; Neurons; Nuclear; Outcome; Oxidation-Reduction; Pathway interactions; Physiological; Property; Quality Control; Recovery; Regenerative capacity; Regulation; Research; Role; Signal Pathway; Signal Transduction; Site; Stimulus; Structure; Synapses; Testing; Therapeutic; activating transcription factor 1; age related; aged; axon injury; axon regeneration; cell motility; experimental study; improved; in vivo; in vivo imaging; innovation; insight; juvenile animal; mutant; nerve damage; nerve injury; nervous system disorder; novel; novel therapeutic intervention; progressive neurodegeneration; response; response to injury; therapeutic development

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.

项目摘要/摘要 线粒体定位的动态调节对各种能量需求和动态平衡至关重要 亚细胞区的维持。控制线粒体运动性、动力学、锚定和 已经确定了质量控制。然而，人们对神经元的信号机制知之甚少。 协调线粒体的短期和长期定位，以响应环境和生理 刺激物。这种对线粒体定位的适当调节在具有独特和 导致线粒体生物合成之间不匹配的根本问题的细长结构 部位(细胞体)和线粒体功能的高要求部位(轴突和突触)。越来越多的证据 表明线粒体对轴突和突触的不规则定位与许多 神经系统疾病，包括阿尔茨海默病、神经退化和再生障碍。这 该提案旨在阐明神经元如何在两种基本条件下调节线粒体的定位 包括年龄和受伤情况。此外，我们建议确定线粒体定位的调节 影响神经功能的维持，防止损伤和衰老。这项建议是基于最近的 活体研究表明，成年神经元的线粒体运动逐渐减少。我们的实验室和其他人 还揭示了损伤的神经元急剧改变线粒体的运动和定位，决定了 轴突再生能力。神经元调节线粒体定位的潜在机制 衰老和受伤情况仍然知之甚少。缺乏这方面的知识阻碍了 阿尔茨海默病和神经损伤等神经疾病的治疗策略 与线粒体定位异常有关。我们结合秀丽隐杆线虫的遗传学， 线粒体生物学、创新的活体成像和激光轴突切断术，以满足这些未得到满足的需求。我们的 初步数据表明，DLK-1 MAPK信号通路是与突触相关的保守途径 阿尔茨海默病模型中的发育、轴突再生和进行性神经变性可能是 神经元中线粒体定位的新调节因子。这项提议包括三个具体目标来回答 神经元如何在衰老和损伤条件下调节线粒体定位(目标1)，其作用是什么？ 线粒体在成年神经元损伤后的恢复(目标2)，以及线粒体之间是如何沟通的 线粒体和细胞核控制DLK-1信号转导，从而实现线粒体功能和轴突再生 (目标3)。我们期望，我们提议的实验将对 在衰老和损伤中通过调节线粒体功能来维持神经系统的最佳功能 神经元。此外，我们的发现将为恢复神经元的新的治疗方法提供更好的见解。 神经损伤后的功能。