Mitochondrial Interactions with the Plasmamembrane: Genetic Underpinnings and Functional Consequences at Drosophila Nerve Terminals.

线粒体与质膜的相互作用：果蝇神经末梢的遗传基础和功能后果。

• 批准号: 10279265
• 负责人: GREGORY TALISKER MACLEOD
• 金额: $ 36.52万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10279265
• 关键词: 3-Dimensional; Adopted; Afferent Neurons; Behavior; Biology; Caenorhabditis elegans; Cell membrane; Cells; Code; Data; Docking; Drosophila genus; Electron Microscopy; Electrons; Endoplasmic Reticulum; Equilibrium; Eukaryota; Face; Failure; Ganglia; Genes; Genetic; Glutamates; Goals; Golgi Apparatus; Individual; Ions; Iron; Knowledge; Laboratories; Larva; Life Cycle Stages; Light; Link; Lipids; Location; Lysosomes; Metabolism; Mitochondria; Mitochondrial Membrane Protein; Modeling; Motor Neurons; Nerve; Neurodegenerative Disorders; Neurologic; Neurons; Neurophysiology - biologic function; Neurotransmitters; Outer Mitochondrial Membrane; Physiology; Positioning Attribute; Power Sources; Presynaptic Terminals; Reporting; Resolution; Role; Scanning Electron Microscopy; Shapes; Site; Structure; Techniques; Testing; Vertebrates; Yeasts; base; density; mitochondrial dysfunction; neurotransmission; neurotransmitter release; novel; peroxisome membrane; presynaptic; presynaptic neurons; tool

ABSTRACT Our overall goal is to elucidate the different mechanisms available to a neuron to control mitochondria at a subcellular level, and the genetic bases of these capabilities. Mitochondria accumulate within nerve terminals where they generate most of the ATP required to package and recycle neurotransmitters and to maintain transmembrane ion-balances. Neural function is reliant on mitochondrial function to sustain neurotransmitter release, and mitochondrial dysfunction is a hallmark of many neurodegenerative diseases. It is therefore imperative to gain a better understanding of the mechanisms that neurons use to control mitochondria at the sub-cellular level of nerve terminals, and how this might differ between neuron types. Here we present the hypothesis that sites at which mitochondria interact with the plasma membrane (PM) represent a form of mitochondrial utilization that confers advantages in those parts of a neuron with high power demands, such as nerve terminals. We propose to elucidate the functional significance of such interactions, and their genetic underpinnings. To do this we are adopting a structure-function approach, exploiting the small size and genetic tools of Drosophila. In Aim 1 we will use serial block face scanning electron microscopy to determine the neuron types, and subcellular regions served by mitochondrial-PM interactions. In Aim 2 we will use a novel form of super-resolution to investigate the formation and disassembly of these interactions, and the functional consequences for presynaptic physiology and neurotransmission. In Aim 3 we will investigate the role of a select group of genes identified as candidates for a role in mitochondrial-PM interactions. The significance of this proposal lies in its potential to uncover novel neuronal and sub-cellular specific mitochondrial functions, and the genetic bases of these functions, which may throw light on the selective neuronal vulnerability observed in different neurodegenerative diseases and neurological conditions.

摘要