Mitochondrial Quality Control by Drp1

Drp1 的线粒体质量控制

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的线粒体通过氧化磷酸化积极产生ATP，并不断经历高水平氧化应激。线粒体的溶酶体降解是抑制积累的关键质量控制线粒体损伤。理解线粒体质量控制至关重要且紧急，因为它的缺陷是与许多神经系统疾病有关，例如阿尔茨海默氏病，帕金森氏病和肌萎缩性侧硬化症。我们的初步数据导致我们假设一个大脑特异性的溶酶体 - DRP1 GTPase的相关同工型称为LysODRP1，可通过增加了这两个细胞器之间的接近度。在此拟议的调查中，我们将对此进行测试两个具体目标中的假设。在第一个目标中，我们将确定lysodrp1如何将线粒体传递到溶酶体（1.1），GTP如何调节Lysodrp1（1.2），以及将LysodRP1募集到溶酶体（1.3）的原因。在第二个目的，我们将确定LysoDRP1在神经元中线粒体周转率中的功能（2.1）， lysodrp1杀伤的质量控制神经元的能量代谢（2.2），以及lysodrp1对神经元的生存（2.3）。为了成功实现这些目标，我们将使用创新的方法 lysodrp1特异性小鼠敲除由CRISPR/CAS9产生的，一种用于传输的荧光生物传感器线粒体到溶酶体和DRP1敲除细胞用单个特定的DRP1同工型重构。这项工作将将线粒体质量控制的机械信息转化为人类疾病的治疗干预措施。