The PINK1 Mitochondrial Signaling Pathway

PINK1 线粒体信号通路

• 批准号: 7810715
• 负责人: LIAN LI
• 金额: $ 29.16万
• 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/7810715
• 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）：线粒体是真核生物普遍存在的动态细胞器，主要参与许多细胞过程，包括能量产生、代谢、氧化还原控制和程序性细胞死亡。线粒体功能障碍是40多种人类疾病的原因，包括癌症、糖尿病、肥胖症、共济失调和神经退行性疾病如帕金森氏病、阿尔茨海默氏病和亨廷顿氏病，这一发现强调了正常发挥功能的线粒体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学中是如何控制的，以及这个过程在疾病状态下是如何失调的。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，但磷酸化在调节线粒体功能中的作用知之甚少。线粒体作为细胞信号的接收、整合和传递中心已被越来越多的人所认识，然而，目前对线粒体信号通路的了解还很少。PTEN诱导的推定激酶1（PINK1）是一种新的线粒体蛋白，最初是在筛选PTEN肿瘤抑制活性的潜在介质中分离出来的。PINK1的表达在具有高转移潜力的黑素瘤和结肠癌细胞中上调的发现也表明了与癌症的联系。最近，PINK1基因突变被确定为早发性常染色体隐性帕金森病的常见原因。在果蝇中，PINK1表达的缺失导致线粒体缺陷以及肌肉和多巴胺能神经元变性。尽管遗传学证据表明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，PINK1的底物仍有待确定。在本项目中，申请人团队将综合运用生物化学、蛋白质组学、分子生物学和细胞生物学方法，研究PINK1在线粒体中的信号传导作用，鉴定PINK1下游效应物，阐明PINK1保护细胞抗凋亡的分子机制。拟议研究的结果应该推进我们对所有真核细胞中线粒体信号传导基本机制的认识，并促进治疗人类线粒体疾病的有效疗法的开发。 公共卫生关系：线粒体功能障碍是导致40多种人类疾病的原因，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状态下如何控制，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。