Role of DJ1 in mitochondrial biogenergetics and neuronal metabolism

描述（由申请人提供）：线粒体功能障碍导致神经退行性疾病，线粒体生物能量学的改善可改善神经元和突触功能障碍。帕金森病（PD）是第二大流行的神经退行性疾病，其临床特征在于正常运动系统控制的丧失以及运动和其他神经系统程序的启动和抑制缺陷。在病理学上，该病症的特征在于黑质内多巴胺能神经元的损失。研究表明，线粒体电子传递和线粒体DNA复制的抑制剂易患PD。家族性疾病约占10%的这种疾病，并告知散发性疾病。蛋白质DJ 1（PARK 7）基因中的几个突变与早发性家族性PD相关，但DJ 1的功能尚未完全了解。DJ 1突变动物表现出对神经元毒素的敏感性增加; DJ 1是不同物种正常寿命、完整运动功能和抗神经元氧化损伤所必需的。线粒体与突变型DJ 1功能障碍有关; DJ 1定位于线粒体，DJ 1突变型线粒体制造ATP的能力降低，呼吸异常。DJ 1突变体线粒体对线粒体通透性转换（mPT）敏感，这是细胞死亡的一个标志，线粒体显示出异常高的状态4呼吸，表明线粒体内膜渗漏。我们假设，DJ 1是产生正常呼吸耦合所必需的。我们的初步研究表明，DJ 1是线粒体偶联所必需的：它与线粒体F1/FO ATP合酶结合，并抑制我们在ATP合酶c亚基环内发现的一种新的泄漏传导通道。在本申请中，我们将确定DJ 1在哺乳动物线粒体中的蛋白结合位点，描述DJ 1易位到线粒体的病理和生理条件，确定DJ 1是否影响线粒体偶联，（通过调节新描述的c-亚基漏导孔）并在小鼠模型中确定DJ 1的功能缺陷是否有助于神经退行性代谢应激，病理性渗透性转变（PT）和细胞死亡。

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.