Milton and the Transport of Mitochondria

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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.