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于各种能量需求和稳态至关重要 维持亚细胞区域。关键组件管理线粒体运动，动力学，锚定和 已经确定了质量控制。但是，关于神经元的信号传导机制知之甚少 响应环境和生理的短期和长期坐标线粒体定位 刺激。在具有独特且 伸长的结构导致线粒体生物合成之间不匹配的基本问题 线粒体功能（轴突和突触）的位点（细胞体）和高需求位点。越来越多的证据 表明在轴突上的线粒体定位不规则，突触与许多人密切相关 神经系统疾病，包括阿尔茨海默氏病，神经变性和再生衰竭。这 建议旨在阐明神经元如何在两个基本条件下调节线粒体定位 包括年龄和伤害。此外，我们建议确定线粒体定位的调节 影响神经元功能的损伤和衰老。该提案是基于最近的 体内研究成年神经元逐渐减少线粒体运动。我们的实验室和其他人 还揭示了受伤的神经元急性改变线粒体运动和定位，确定 轴突再生能力。神经元调节线粒体定位的基本机制 衰老和伤害状况仍然很少了解。缺乏这种知识阻碍了 神经疾病的治疗策略，例如阿尔茨海默氏病和神经损伤 与线粒体定位异常有关。我们结合了秀丽隐杆线虫遗传学的结合， 线粒体生物学，创新的体内成像和激光轴切开术，以满足这些未满足的需求。我们的 初步数据表明DLK-1 MAPK信号传导，一种与突触相关的保守途径 在阿尔茨海默氏病模型中的发展，轴突再生和进行性神经退行性变化可能是 神经元中线粒体定位的新型调节剂。该提案包括三个特定的目的 神经元如何调节衰老和损伤条件下的线粒体定位（AIM 1），什么作用 线粒体在受伤后恢复成人神经元（AIM 2）以及如何之间 线粒体和核控制DLK-1信号传导，从而将线粒体功能和轴突再生 （目标3）。我们希望我们提出的实验将对机制有了新的理解 通过调节衰老和受伤的线粒体功能来保持神经系统的最佳功能 神经元。此外，我们的发现将更好地了解恢复神经元的新型治疗方法 神经损伤后的功能。