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: 10443879
• 负责人: GREGORY TALISKER MACLEOD
• 金额: $ 37.01万
• 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/10443879
• 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.

抽象的 我们的总体目标是阐明神经元控制线粒体的不同机制 在亚细胞水平上，以及这些能力的遗传基础。线粒体在神经内积聚 它们产生包装和回收神经递质所需的大部分 ATP 的终端 以维持跨膜离子平衡。神经功能依赖于线粒体功能来维持 神经递质释放和线粒体功能障碍是许多神经退行性疾病的标志 疾病。因此，必须更好地了解神经元使用的机制 在神经末梢的亚细胞水​​平上控制线粒体，以及这在神经末梢之间有何不同 神经元类型。在这里，我们提出这样的假设：线粒体与血浆相互作用的位点 膜（PM）代表了线粒体利用的一种形式，它为线粒体的这些部分提供了优势 具有高功率需求的神经元，例如神经末梢。我们建议阐明功能 这种相互作用的重要性及其遗传基础。为此，我们采用 结构功能方法，利用果蝇的小尺寸和遗传工具。在目标 1 中，我们将 使用串行块面扫描电子显微镜确定神经元类型和亚细胞 线粒体-PM 相互作用所服务的区域。在目标 2 中，我们将使用一种新颖的超分辨率形式 研究这些相互作用的形成和分解，以及功能性后果 突触前生理学和神经传递。在目标 3 中，我们将调查一组选定的角色的作用 被确定为在线粒体-PM 相互作用中发挥作用的候选基因。此举的意义 提议在于它有可能发现新的神经元和亚细胞特异性线粒体功能， 以及这些功能的遗传基础，这可能有助于揭示选择性神经元脆弱性 在不同的神经退行性疾病和神经系统疾病中观察到。