Milton and the Transport of Mitochondria

弥尔顿和线粒体的运输

• 批准号: 7117684
• 负责人: Thomas L. Schwarz
• 金额: $ 28.88万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117684
• 关键词: Drosophilidae; RNA splicing; axon; cell line; chemical kinetics; cytoskeleton; dendrites; electron microscopy; embryo /fetus; fluorescence microscopy; gene expression; genetic regulation; glycosylation; intermolecular interaction; kinesin; larva; mitochondria; nerve /myelin protein; neuronal transport; neurons; neuroregulation; phosphorylation; protein localization; protein structure function; video microscopy

DESCRIPTION (provided by applicant): Motor proteins move organelles within the cytoplasm of cells and thereby contribute to the appropriate distribution of those organelles. The motors involved, including members of the kinesin family, are of considerable interest from the cell biological point of view: how do motors couple to their appropriate cargos?; how do they direct those cargos to particular locations?; how is their activity regulated?; how is the proper distribution of the organelle achieved and maintained? The proper distribution of an organelle can pose a complex problem for a cell. Defects in this process can cause peripheral neuropathies and have been implicated in some neurodegenerative diseases. Mitochondria are highly mobile organelles. They must distribute themselves within cells so as to be able to supply sufficient energy to each part of a cell to match the needs of that part. The movement of mitochondria up and down axons and dendrites of neurons is one of the most dramatic examples of mitochondrial transport. In a Drosophila mutant called milton, mitochondria are completely absent from nerve axons and terminals. The protein encoded by the milton gene is found on mitochondria and is associated with the motor protein kinesin. The present proposal seeks to understand the role of Milton in the transport of mitchondria within neurons and other cells. The first aim, involving primarily fluorescent and video microscopy, seeks to determine what forms of transport require Milton and to determine if Milton is on all mitochondria or only those that are undergoing transport. The subsequent aims probe the mechanism of Milton action, primarily through biochemical studies. They inquire how Milton is localized to mitochondria, how Milton interacts with kinesin, and whether Milton serves as an adaptor that links kinesin to the mitochondrion. In the process, the proposal also examines the alternative splicing of the Milton gene and the potential regulatory role of post-translational modifications of Milton.

描述（由申请人提供）：运动蛋白在细胞的细胞质内移动细胞器，从而有助于这些细胞器的适当分布。从细胞生物学的角度来看，所涉及的马达，包括驱动蛋白家族的成员，引起了相当大的兴趣：马达如何与其适当的货物耦合？他们如何将这些货物运送到特定地点？他们的活动如何受到监管？如何实现和维持细胞器的正确分布？细胞器的正确分布会给细胞带来复杂的问题。这一过程的缺陷可能导致周围神经病变，并与一些神经退行性疾病有关。线粒体是高度移动的细胞器。它们必须将自己分布在细胞内，以便能够向细胞的每个部分提供足够的能量，以满足该部分的需要。线粒体在神经元轴突和树突上上下运动是线粒体运输最引人注目的例子之一。在一种名为 Milton 的果蝇突变体中，神经轴突和末端完全不存在线粒体。 milton 基因编码的蛋白质存在于线粒体上，并与运动蛋白驱动蛋白相关。本提案旨在了解米尔顿在神经元和其他细胞内线粒体运输中的作用。第一个目标主要涉及荧光和视频显微镜，旨在确定哪种形式的运输需要 Milton，并确定 Milton 是否存在于所有线粒体上或仅存在于正在运输的线粒体上。随后的目标主要是通过生化研究来探索 Milton 的作用机制。他们询问 Milton 如何定位于线粒体、Milton 如何与驱动蛋白相互作用，以及 Milton 是否作为连接驱动蛋白和线粒体的适配器。在此过程中，该提案还考察了 Milton 基因的选择性剪接以及 Milton 翻译后修饰的潜在调控作用。