The PINK1 Mitochondrial Signaling Pathway

PINK1 线粒体信号通路

• 批准号: 7907111
• 负责人: LIAN LI
• 金额: $ 27.34万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907111
• 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）：线粒体是真核生物中普遍存在的动态细胞器，关键参与许多细胞过程，包括能量产生、代谢、氧化还原控制和程序性细胞死亡。研究结果强调了线粒体功能正常对人类健康的重要性：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、共济失调以及帕金森病、阿尔茨海默病和亨廷顿病等神经退行性疾病。这项研究的长期目标是在分子水平上了解正常生理中线粒体功能如何受到控制，以及该过程在疾病状态下如何失调。尽管可逆的蛋白质磷酸化是控制许多细胞过程的主要机制，但人们对磷酸化在调节线粒体功能中的作用知之甚少。线粒体越来越被认为是接收、整合和传输细胞信号的中心，然而，目前人们对线粒体信号通路知之甚少。 PTEN 诱导的推定激酶 1 (PINK1) 是一种新型线粒体蛋白，最初是在筛选 PTEN 肿瘤抑制活性的潜在介质时分离出来的。 PINK1 的表达在具有高转移潜力的黑色素瘤和结肠癌细胞中上调的发现也表明与癌症有关。最近，PINK1 基因突变被确定为早发型常染色体隐性遗传帕金森病的常见原因。在果蝇中，PINK1 表达缺失会导致线粒体缺陷以及肌肉和多巴胺能神经元变性。尽管遗传证据表明 PINK1 在细胞存活中发挥重要作用，但 PINK1 如何调节线粒体功能尚不清楚，并且 PINK1 的底物仍有待确定。在该项目中，申请人团队将综合运用生化、蛋白质组学、分子和细胞生物学方法来研究PINK1在线粒体中的信号传导作用，鉴定PINK1下游效应子，并阐明PINK1保护细胞免于凋亡的分子机制。拟议研究的结果应增进我们对所有真核细胞线粒体信号传导基本机制的了解，并促进开发治疗人类线粒体疾病的有效疗法。 公共卫生相关性：线粒体功能障碍导致 40 多种人类疾病，包括帕金森病、阿尔茨海默病、糖尿病和癌症，这一发现强调了线粒体功能正常对人类健康的重要性。拟议研究的目标是在分子水平上了解线粒体功能在正常生理学中如何受到控制以及该过程在疾病状态下如何变得失调。拟议研究的结果将为开发治疗人类多种线粒体疾病的有效疗法提供所需的基本信息。