The Life History of Mitochondria in Neurons

描述(申请人提供)：线粒体是半自主细胞器，对所有哺乳动物组织的功能都是必不可少的。为了支持细胞功能，线粒体必须被运送到需要能量的地方，并可能在它们的有效寿命结束时被取回。神经元的结构是这样的，从投射神经元的远端部分有效地传递和检索线粒体是一项重大的挑战和非凡的成就。然而，在中枢神经元的背景下，人们对迎接这一挑战的机制以及线粒体出生、生和死的最基本信息知之甚少。该项目的中心论点是：(A)线粒体的正常产生、传递、恢复和降解(统称为线粒体稳态)对于维持神经元功能是必不可少的；(B)这些过程受到调控，以支持神经元功能的变化；(C)神经毒素可能通过干扰其中一个或多个过程而部分地损伤神经元。我们将在以下实验问题中开始解决这些概念：1)健康神经元中线粒体传递和检索的基本特性是什么？2)神经毒素是否改变线粒体的运动？3)线粒体的生物发生是否仅限于神经元细胞体，以及损伤是否改变了线粒体的生物发生？4)线粒体在哪里降解？解决这些问题将提供对中枢神经元线粒体生活史的前所未有的洞察，并将突出一个重要的新参数，以供考虑神经退行性疾病的机制。

DESCRIPTION (provided by applicant): Mitochondria are semi-autonomous organelles essential for the function of all mammalian tissues. In order to support cell function, mitochondria have to be delivered to the site of energy demand, and are presumably retrieved when they reach the end of their effective life. The architecture of neurons is such that the effective delivery and retrieval of mitochondria from the distal parts of projection neurons represents a significant challenge and a remarkable accomplishment. However, the mechanisms by which this challenge is met, together with the most basic information of the birth, life and death of mitochondria, is poorly understood in the context of central neurons. The central theses of this project are (a) that the normal generation, delivery, retrieval and degradation of mitochondria (collectively termed "mitochondrial homeostasis") are essential for the maintenance of neuronal function, (b) that these processes are regulated to support changes in neuronal function, and (c) that neurotoxins may injure neurons in part by interfering with one or more of these processes. We will start to address these concepts in the following experimental questions: 1) What are the basic properties of mitochondrial delivery and retrieval in healthy neurons? 2) Do neurotoxins alter mitochondrial movement?, 3) Is mitochondrial biogenesis restricted to neuronal cell bodies, and is biogenesis altered by injury? and 4) Where are mitochondria degraded? Addressing these questions will provide an unprecedented insight into the life history of mitochondria in central neurons, and will highlight an important new parameter for consideration in the mechanism underlying neurodegenerative disease.