The Life History of Mitochondria in Neurons

描述（由申请人提供）：线粒体是所有哺乳动物组织功能所必需的半自主细胞器。为了支持细胞功能，线粒体必须被运送到需要能量的地方，当它们达到有效寿命的终点时，可能会被回收。神经元的结构是这样的，从投射神经元的远端有效地传递和提取线粒体是一个重大的挑战和显著的成就。然而，在中枢神经元的背景下，这一挑战的机制，以及线粒体的诞生、生存和死亡的最基本信息，都知之甚少。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”）对维持神经元功能至关重要，(b)这些过程受到调节以支持神经元功能的变化，以及(c)神经毒素可能通过干扰一个或多个这些过程来部分损伤神经元。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恢复的基本特性是什么？2)神经毒素会改变线粒体运动吗？3)线粒体的生物发生是否局限于神经元细胞体，生物发生是否因损伤而改变？4)线粒体在哪里降解？解决这些问题将为了解中枢神经元线粒体的生活史提供前所未有的见解，并将突出一个重要的新参数，以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.