The PINK1 Mitochondrial Signaling Pathway

PINK1 线粒体信号通路

• 批准号: 7660445
• 负责人: LIAN LI
• 金额: $ 29.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-18 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660445
• 关键词: Alzheimer' s Disease; Antioxidants; Apoptosis; Ataxia; Biochemical; Biological; Brain; Cell Survival; Cell physiology; Cells; Cessation of life; Colon Carcinoma; Cytoprotection; Data; Defect; Development; Diabetes Mellitus; Disease; Drosophila genus; Enzymes; Eukaryotic Cell; Gene Mutation; Genes; Genetic; Goals; Health; Human; Huntington Disease; Knowledge; Lead; Life; Link; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolism; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Molecular; Molecular Chaperones; Muscle; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Obesity; Organelles; Organism; Oxidation-Reduction; Oxidative Stress; PTEN gene; PTEN-induced putative kinase; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Physiology; Post-Translational Protein Processing; Process; Production; Proteomics; Regulation; Research; Role; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic; Therapeutic Intervention; dopaminergic neuron; early onset; effective therapy; enzyme activity; human disease; insight; loss of function; lymphoblast; melanoma; mitochondrial dysfunction; novel; protein expression; public health relevance; tumor

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.

描述（由申请人提供）：线粒体是无核生物的无处不在和动态细胞器，这些细胞体与许多细胞过程有关，包括能量产生，代谢，氧化还原控制和程序性细胞死亡。线粒体功能障碍造成了40多种人类疾病，包括癌症，糖尿病，肥胖症，共济失调以及神经退行性疾病，例如帕金森氏症，阿尔茨海默氏病和匈奴顿的疾病。这项研究的长期目标是在分子水平上了解线粒体功能如何在正常生理学中控制，以及在疾病状态下该过程如何失调。尽管可逆的蛋白质磷酸化是控制众多细胞过程的主要机制，但磷酸化在调节线粒体功能中的作用尚不清楚。线粒体越来越多地被认为是接收，整合和传输细胞信号的中心，但是，目前对线粒体信号通路的了解很少。 PTEN诱导的假定激酶1（PINK1）是一种新型的线粒体蛋白，最初是在筛选中分离出来的PTEN肿瘤抑制活性的潜在介体。发现PINK1在具有高转移性潜力的黑色素瘤和结肠癌细胞中上调的PINK1的表达也表明了与癌症的联系。最近，Pink1基因中的突变被确定为出现早期，常染色体隐性帕金森氏病的常见原因。在果蝇中，PINK1表达的丧失导致线粒体缺陷，肌肉和多巴胺能神经元变性。尽管遗传证据表明PINK1在细胞存活中的重要作用，但PINK1如何调节线粒体功能尚不清楚，并且PINK1的底物仍有待鉴定。在该项目中，申请人的团队将使用生化，蛋白质组学，分子和细胞生物学方法的组合来研究PINK1在线粒体中的信号传导作用，鉴定PINK1下游效应子，并阐明PINK1通过这些机制保护细胞的分子机制。拟议的研究的结果应提高我们对所有真核细胞中线粒体信号传导的基本机制的了解，并促进开发有效治疗人类线粒体疾病的疗法。 公共卫生相关性：线粒体功能障碍造成40多种人类疾病，包括帕金森氏病，阿尔茨海默氏病，糖尿病和癌症，使线粒体功能障碍造成40多种人类疾病的研究结果，强调了线粒体对人类健康的重要性。拟议的研究的目的是在分子水平上了解线粒体功能如何在正常生理学中控制，以及在疾病状态下该过程如何失调。拟议研究的结果将提供开发有效治疗剂的基本信息，以治疗人类中的许多线粒体疾病。