The PINK1 Mitochondrial Signaling Pathway

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。线粒体功能紊乱导致40多种人类疾病，包括癌症、糖尿病、肥胖、共济失调和神经退行性疾病，如帕金森氏症、阿尔茨海默氏症和亨廷顿氏病，这一发现强调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了解，在分子水平上，线粒体功能是如何在正常生理状态下被控制的，以及这个过程是如何在疾病状态下变得失调的。虽然可逆蛋白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尚不清楚。线粒体作为接收、整合和传递细胞信号的中心已被越来越多地认识到，然而，目前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在高转移潜能的黑色素瘤和结肠癌细胞中表达上调，这一发现也提示了它与癌症的联系。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表达缺失导致线粒体缺陷和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，PINK1的底物仍有待鉴定。在本项目中，申请者团队将结合生物化学、蛋白质组学、分子和细胞生物学的方法来研究PINK1在线粒体中的信号作用，鉴定PINK1的下游效应物，阐明PINK1保护细胞免于凋亡的分子机制。拟议的研究结果将促进我们对所有真核细胞中线粒体信号传导的基本机制的认识，并促进治疗人类线粒体疾病的有效疗法的发展。

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.