Role of DJ1 in mitochondrial biogenergetics and neuronal metabolism

DJ1 在线粒体生物发生学和神经元代谢中的作用

基本信息

批准号：
8743398
负责人：
Elizabeth Ann Jonas
金额：
$ 45.79万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8743398
关键词：
ATP Synthesis Pathway Accounting Affect Animals Binding Binding Sites Bioenergetics Calcium Cell Death Cells Consumption Coupling DNA biosynthesis Defect Disease Electron Transport Etiology Familial disease Functional disorder Gene Mutation Gene Proteins Generations Glutamates Hallmark Cell Inner mitochondrial membrane Ion Channel Longevity Measures Membrane Membrane Potentials Metabolic Metabolic stress Metabolism Mitochondria Mitochondrial DNA Motor Mus Mutation Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neuronal Dysfunction Neurons PARK7 gene Parkinson Disease Permeability Physiological Protein Binding Rattus Recombinant Proteins Reporting Resistance Respiration Role Substantia nigra structure Synapses System Toxin Vesicle biophysical properties dopaminergic neuron early onset immunoreactivity inhibitor/antagonist insight mitochondrial dysfunction mitochondrial membrane mitochondrial permeability transition pore mouse model mutant neuronal excitability novel oxidative damage pars compacta patch clamp prevent programs promoter public health relevance respiratory small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial dysfunction contributes to neurodegenerative disorders, and improvement of mitochondrial bioenergetics may ameliorate neuronal and synaptic dysfunction. Parkinson's Disease (PD) is the second most prevalent neurodegenerative disease, characterized clinically by loss of normal motor system control and by defects in initiation and inhibition of motor and other nervous system programs. Pathologically, the disorder is characterized by loss of dopaminergic neurons within the substantia nigra pars compacta. Studies show that inhibitors of mitochondrial electron transport and of mitochondrial DNA replication predispose to the onset of PD. Familial disorders account for approximately 10% of this disorder and inform on sporadic disease. Several mutations in the gene for the protein DJ1 (PARK7) are associated with early-onset familial PD but the function of DJ1 has been incompletely understood. DJ1 mutant animals show increased sensitivity to neuronal toxins; DJ1 is required in different species for normal life span, intact motor function and resistance to neuronal oxidative damage. Mitochondria are implicated in mutant DJ1 dysfunction; DJ1 localizes to mitochondria and DJ1 mutant mitochondria have decreased ability to make ATP and abnormal respiration. DJ1 mutant mitochondria are sensitive to mitochondrial permeability transition (mPT), one hallmark of cell death, and mitochondria demonstrate abnormally high state 4 respiration, indicative of a leaky mitochondrial inner membrane. We hypothesize that DJ1 is required for the generation of normal respiratory coupling. Our preliminary studies have suggested that DJ1 is necessary for mitochondrial coupling: It binds to the mitochondrial F1/FO ATP synthase and inhibits a novel leak conductance channel that we have discovered within the ATP synthase c-subunit ring. In this application, we will determine the protein binding site for DJ1 in mammalian mitochondria, delineate pathological and physiological conditions under which DJ1 translocates to mitochondria, determine if DJ1 influences mitochondrial coupling (by regulating a newly described c-subunit leak conductance pore) and determine in mouse models if functional deficiency of DJ1 contributes to neurodegenerative metabolic stress, pathological permeability transition (PT) and cell death.

描述（由申请人提供）：线粒体功能障碍会导致神经退行性疾病，并改善线粒体生物能力可能会改善神经元和突触功能障碍。帕金森氏病（PD）是第二大流行的神经退行性疾病，其特征在临床上以正常运动系统控制以及运动和其他神经系统程序的启动和抑制作用的缺陷。从病理上讲，该疾病的特征是底虫pars pars compacta中多巴胺能神经元的丧失。研究表明，线粒体电子转运和线粒体DNA复制的抑制剂倾向于PD发作。家族疾病约占这种疾病的10％，并了解了零星疾病。蛋白质DJ1（PARK7）基因中的几个突变与早发性家族性PD有关，但DJ1的功能尚不完全了解。 DJ1突变动物表现出对神经元毒素的敏感性提高。在不同的物种中，需要DJ1的正常寿命，完整的运动功能以及对神经氧化损伤的耐药性。线粒体与突变的DJ1功能障碍有关。 DJ1定位于线粒体和DJ1突变体线粒体的降低的ATP和异常呼吸的能力。 DJ1突变体线粒体对线粒体通透性过渡（MPT），细胞死亡的一个标志和线粒体敏感，表现出异常高的状态4呼吸，表明线粒体内部膜渗漏。我们假设DJ1是正常呼吸耦合所必需的。我们的初步研究表明，DJ1对于线粒体耦合是必不可少的：它与线粒体F1/FO ATP合酶结合，并抑制我们在ATP合酶C-Subunit环中发现的新型泄漏电导通道。在此应用中，我们将确定哺乳动物线粒体中DJ1的蛋白质结合位点，划定的病理和生理条件，DJ1易位到线粒体，确定DJ1是否会影响线粒体耦合（通过调节新型C-Subunit渗漏孔的启用dj dij dij dij dij formitiation dij）是否影响线粒体耦合（是否影响）。压力，病理渗透性转变（PT）和细胞死亡。