Mitochondrial Fission and Liver Function

线粒体裂变与肝功能

基本信息

批准号：
8466000
负责人：
YISANG YOON
金额：
$ 16.6万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2014-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial dysfunction is a major cause of liver pathology by participating in oxidative stress and cell death. Mitochondria continually change their morphology and location inside the cell. Dynamic changes in mitochondrial morphology involve mainly fission and fusion of mitochondrial tubules. However, the functional significance of the dynamic behavior of mitochondria is not well understood. The mitochondrial electron transport chain (ETC) is the major source of reactive oxygen species (ROS) that contributes to oxidative stress conditions. Our studies have demonstrated that inhibiting mitochondrial fission decreases cellular ROS levels in ROS-overproducing conditions, which in turn reduces oxidative stress-induced cell death. Our long-term objectives are to elucidate molecular mechanisms of mitochondrial fission/fusion, and to define the physiological roles of mitochondrial dynamics. In this application, we will continue to study the molecular mechanisms of how mitochondrial fission and fusion proteins control mitochondrial morphology, and investigate the role of mitochondrial dynamics in mitochondrial activity and liver function. The central hypothesis of this proposal is that networks of molecular interactions involving fission and fusion proteins on the mitochondrial membrane regulate mitochondrial morphology and function, and play an integral role in health and pathology of the liver. In the first specific aim, we will study the molecular mechanisms that control the fission/fusion balance of mitochondria. In the second specific aim, we will investigate the involvement of the mitochondrial fission protein hFis1 in mitochondrial fission and apoptosis. The third specific aim is to understand the physiological significance of mitochondrial morphology by focusing on its relationship with the ETC activity and ROS generation in hepatocytes. We will also test whether mitochondrial fission can be a useful target to control liver injury using a cholestatic liver model how mitochondrial dynamics contribute to the regulation of mitochondrial function and cell physiology in health and diseases of the liver. PUBLIC HEALTH RELEVANCE: Growing evidence indicates that control of mitochondrial morphology is a fundamental cellular process determining cell life and death, and we believe that information from these studies will greatly increase our understanding of how mitochondrial dynamics contribute to the regulation of mitochondrial function and cell physiology in health and diseases of the liver.

描述（由申请人提供）：线粒体功能障碍是参与氧化应激和细胞死亡的主要原因。线粒体不断改变其形态和细胞内部的位置。线粒体形态的动态变化主要涉及线粒体小管的裂变和融合。但是，线粒体动态行为的功能意义尚不清楚。线粒体电子传输链（ETC）是有助于氧化应激条件的活性氧（ROS）的主要来源。我们的研究表明，抑制线粒体裂变会在ROS超过产生的条件下降低细胞ROS水平，从而减少氧化应激诱导的细胞死亡。我们的长期目标是阐明线粒体裂变/融合的分子机制，并定义线粒体动力学的生理作用。在此应用中，我们将继续研究线粒体裂变和融合蛋白如何控制线粒体形态的分子机制，并研究线粒体动力学在线粒体活性和肝功能中的作用。该提议的中心假设是，线粒体膜上涉及裂变和融合蛋白的分子相互作用网络调节线粒体形态和功能，并在肝脏健康和病理中起着不可或缺的作用。在第一个特定目的中，我们将研究控制线粒体裂变/融合平衡的分子机制。在第二个特定目的中，我们将研究线粒体裂变蛋白HFIS1在线粒体裂变和凋亡中的参与。第三个具体目的是通过关注其与肝细胞中的ETC活性和ROS产生的关系来了解线粒体形态的生理意义。我们还将测试线粒体裂变是否可以使用胆汁淤积性肝模型来控制肝损伤的有用靶标，线粒体动力学如何有助于调节线粒体功能和细胞生理学在健康和肝脏疾病中的细胞生理。公共卫生相关性：越来越多的证据表明，控制线粒体形态是决定细胞生命和死亡的基本细胞过程，我们认为，这些研究中的信息将大大提高我们对线粒体动力学如何对线粒体功能和肝脏疾病的细胞功能和细胞生理的调节的理解。