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.

抽象的 我们的总体目标是阐明神经元可用的不同机制来控制线粒体 在亚细胞水平以及这些能力的遗传基础上。线粒体在神经内积聚 它们生成包装和回收神经递质所需的大部分ATP的终端 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，线粒体功能障碍是许多神经退行性的标志 疾病。因此，必须更好地了解神经元使用的机制 控制神经末端的亚细胞水​​平的线粒体，这可能会有所不同 神经元类型。在这里，我们提出了线粒体与血浆相互作用的位点的假设 膜（PM）代表一种线粒体利用形式 具有高功率需求的神经元，例如神经终端。我们建议阐明功能 这种相互作用的意义及其遗传基础。为此，我们采用了 结构功能方法，利用了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相互作用提供的区域。在AIM 2中，我们将使用一种新颖的超级分辨率 调查这些相互作用的形成和拆卸，以及对 突触前生理和神经传递。在AIM 3中，我们将调查一组选定组的作用 基因被确定为候选线粒体-PM相互作用的候选者。这一点的意义 提案在于它有可能发现新颖的神经元和亚细胞特异性线粒体功能的潜力， 以及这些功能的遗传基础，这可能会引起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。