Mitochondrial Quality Control by Drp1

Drp1 的线粒体质量控制

• 批准号: 9889969
• 负责人: Hiromi Sesaki
• 金额: $ 31.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889969
• 关键词: Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Axon; Binding Proteins; Biochemical; Biosensor; Brain; CRISPR/Cas technology; Cells; Chemicals; Data; Defect; Degradation Pathway; Dendrites; Disease; Dynamin; Ectopic Expression; Electron Transport; Energy Metabolism; GTP Binding; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Health; Hippocampus (Brain); Human; Hydrolysis; Hypoxia; Individual; Investigation; Knock-out; Knockout Mice; Link; Lysosomes; Maintenance; Measures; Mediating; Membrane Potentials; Membrane Proteins; Mitochondria; Monomeric GTP-Binding Proteins; Morphology; Mus; Neurodegenerative Disorders; Neurons; Organelles; Oxidative Phosphorylation; Oxidative Stress; Oxygen Consumption; PINK1 gene; Parkinson Disease; Pathway interactions; Play; Property; Protein Isoforms; Proteins; Quality Control; Reactive Oxygen Species; Regulation; Respiration; Role; Short-Term Memory; Stress; Tail; Testing; Therapeutic Intervention; Translating; Transport Process; Vesicle; Work; human disease; innovation; insight; mitochondrial autophagy; mutant; nervous system disorder; novel; parkin gene/protein; reconstitution; recruit; response; syntaxin

Abstract Mitochondria actively generate ATP via oxidative phosphorylation and constantly undergo high levels of oxidative stress. Lysosomal degradation of mitochondria is a key quality control that inhibits the accumulation of mitochondrial damage. Understanding mitochondrial quality control is critical and urgent because its defects have been linked to many neurological disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Our preliminary data led us to hypothesize that a brain-specific, lysosome- associated isoform of Drp1 GTPase, termed lysoDrp1, enhances transport of mitochondria to lysosomes by increasing the proximity between these two organelles. In this proposed investigation, we will test this hypothesis in two specific aims. In the first aim, we will determine how lysoDrp1 delivers mitochondria into lysosomes (1.1), how GTP regulates lysoDrp1 (1.2), and what recruits lysoDrp1 to lysosomes (1.3). In the second aim, we will determine the function of lysoDrp1 in mitochondrial turnover in neurons (2.1), the role of lysoDrp1-meidated quality control for energy metabolism in neurons (2.2), and the impact of lysoDrp1 on the survival of neurons (2.3). To successfully accomplish these aims, we will use innovative approaches including lysoDrp1-specific mouse knockout generated by CRISPR/Cas9, a fluorescent biosensor for the transport of mitochondria to lysosomes and Drp1-knockout cells reconstituted with single, specific Drp1 isoforms. This work will have a significant impact on translating the mechanistic information of mitochondrial quality control into therapeutic interventions for human diseases.

摘要 线粒体通过氧化磷酸化积极产生ATP，并不断经历高水平的磷酸化。 氧化应激线粒体的溶酶体降解是抑制蓄积的关键质量控制 线粒体损伤了解线粒体质量控制是关键和紧迫的，因为它的缺陷 与许多神经系统疾病有关，如阿尔茨海默病，帕金森病， 肌萎缩侧索硬化症我们的初步数据让我们假设一个大脑特异性的溶酶体- Drp 1 GT3的相关亚型，称为lysoDrp 1，通过以下途径增强线粒体向溶酶体的转运： 增加了这两个细胞器之间的距离。在这项拟议的调查中，我们将测试 假设有两个具体目标。在第一个目标中，我们将确定lysoDrp 1如何将线粒体递送到 溶酶体（1.1），GTP如何调节lysoDrp 1（1.2），以及什么将lysoDrp 1招募到溶酶体（1.3）。在 第二个目标，我们将确定lysoDrp 1在神经元线粒体更新中的功能（2.1）， lysoDrp 1-神经元能量代谢的质量控制（2.2），以及lysoDrp 1对神经元能量代谢的影响。 神经元的存活（2.3）。为了成功实现这些目标，我们将采用创新方法，包括 通过CRISPR/Cas9产生的lysoDrp 1特异性小鼠敲除，这是一种用于转运 线粒体到溶酶体和用单个特异性Drp 1同种型重建的Drp 1敲除细胞。这项工作 将对将线粒体质量控制的机制信息转化为 人类疾病的治疗干预。