The PINK1 Mitochondrial Signaling Pathway

描述(申请人提供)：线粒体是真核生物中普遍存在的动态细胞器，参与许多细胞过程，包括能量产生、新陈代谢、氧化还原控制和细胞程序性死亡。线粒体功能障碍导致40多种人类疾病，包括癌症、糖尿病、肥胖症、共济失调以及帕金森氏症、阿尔茨海默氏症和亨廷顿病等神经退行性疾病，这一发现突显了线粒体功能正常对人类健康的重要性。这项研究的长期目标是在分子水平上了解线粒体功能在正常生理中是如何受到控制的，以及这一过程在疾病状态下是如何变得失调的。虽然可逆的蛋白质磷酸化是控制许多细胞过程的主要机制，但对磷酸化在调节线粒体功能中的作用却知之甚少。线粒体被认为是接收、整合和传递细胞信号的中心，但目前对线粒体信号转导途径知之甚少。PTEN诱导的假定激酶1(PINK1)是一种新的线粒体蛋白，最初是从筛选PTEN抑制肿瘤活性的潜在介质中分离出来的。PINK1在黑色素瘤和高转移潜能的结肠癌细胞中表达上调，这也表明PINK1与癌症有关。最近，PINK1基因突变被确认为早发性常染色体隐性遗传性帕金森病的常见原因。在果蝇中，PINK1的表达缺失会导致线粒体缺陷以及肌肉和多巴胺能神经元的退化。尽管遗传证据表明PINK1在细胞存活中起着重要作用，但PINK1如何调节线粒体功能尚不清楚，其底物仍有待确定。在这个项目中，申请人的团队将结合生化、蛋白质组学、分子和细胞生物学方法来研究PINK1在线粒体中的信号转导作用，确定PINK1下游效应因子，并阐明PINK1保护细胞免受凋亡的分子机制。这些研究的结果将促进我们对所有真核细胞中控制线粒体信号转导的基本机制的了解，并有助于开发有效的治疗人类线粒体疾病的方法。 公共卫生相关性：线粒体功能正常对人类健康的重要性得到了强调，因为有研究发现，线粒体功能障碍导致了40多种人类疾病，包括帕金森氏症、阿尔茨海默病、糖尿病和癌症。这项拟议的研究的目标是在分子水平上了解线粒体功能在正常生理状态下是如何受到控制的，以及这一过程在疾病状态下是如何变得失调的。建议的研究结果将为开发有效的治疗人类多种线粒体疾病的方法提供所需的基本信息。

DESCRIPTION (provided by applicant): Mitochondria are ubiquitous and dynamic organelles of eukaryotic organisms critically involved in many cellular processes, including energy production, metabolism, redox control, and programmed cell death. The importance of properly functioning mitochondria to human health is underscored by the findings that mitochondrial dysfunction is responsible for more than 40 human diseases, including cancer, diabetes, obesity, ataxia, and neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases. The long-term goal of this research is to understand, at the molecular level, how mitochondrial function is controlled in normal physiology, and how this process becomes dysregulated in disease states. Although reversible protein phosphorylation is a major mechanism for controlling numerous cellular processes, the role of phosphorylation in regulating mitochondrial function is poorly understood. Mitochondria has been increasingly recognized as centers for receiving, integrating, and transmitting cellular signals, however, very little is presently known about mitochondrial signaling pathways. PTEN- induced putative kinase 1 (PINK1) is a novel mitochondrial protein initially isolated in a screen for potential mediators of the tumor-suppressive activity of PTEN. A connection to cancer is also suggested by the finding that the expression of PINK1 is up-regulated in melanoma and colon carcinoma cells with high metastatic potential. Recently, mutations in the PINK1 gene were identified as a common cause for early- onset, autosomal recessive Parkinson's disease. In Drosophila, loss of PINK1 expression leads to mitochondrial defects and muscle and dopaminergic neuron degeneration. Despite the genetic evidence indicating an essential role of PINK1 in cell survival, how PINK1 regulates mitochondrial function is unknown and the substrates of PINK1 remain to be identified. In this project, the applicant's team will use a combination of biochemical, proteomic, molecular and cell biological approaches to investigate the signaling role of PINK1 in mitochondria, identify PINK1 downstream effectors, and elucidate the molecular mechanisms by which PINK1 protects cells against apoptosis. The results of the proposed studies should advance our knowledge of the fundamental mechanisms governing mitochondrial signaling in all eukaryotic cells, and facilitate the development of effective therapies for treating human mitochondrial diseases. PUBLIC HEALTH RELEVANCE: The importance of properly functioning mitochondria to human health is underscored by the findings that mitochondrial dysfunction is responsible for more than 40 human diseases, including Parkinson's disease, Alzheimer's disease, diabetes, and cancer. The goal of the proposed research is to understand, at the molecular level, how mitochondrial function is controlled in normal physiology and how this process becomes dysregulated in disease states. The results of the proposed studies will provide fundamental information needed for the development of effective therapeutics to treat numerous mitochondrial diseases in human.