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能量需求的部位，并且当它们达到有效寿命的终点时可能会被取回。神经元的结构使得从投射神经元的远端部分有效地递送和取回线粒体代表了重大的挑战和显著的成就。然而，在中枢神经元的背景下，人们对这一挑战的机制以及线粒体的出生、生活和死亡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、递送、回收和降解（统称为“线粒体稳态”）对于维持神经元功能是必不可少的，（B）这些过程被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这些过程中的一个或多个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)神经毒素会改变线粒体运动吗？3)线粒体的生物合成是否仅限于神经元细胞体，损伤是否改变了生物合成？线粒体在哪里降解？解决这些问题将提供一个前所未有的深入了解线粒体在中枢神经元的生活史，并将突出一个重要的新参数，考虑在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.