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

摘要 我们的总体目标是阐明神经元控制线粒体的不同机制 以及这些能力的遗传基础。线粒体在神经内积聚 末端，在那里它们产生包装和回收神经递质所需的大部分ATP， 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，更好地了解神经元使用的机制是非常必要的 在神经末梢的亚细胞水平上控制线粒体，以及这在 神经元类型在这里，我们提出的假设，在该网站的线粒体与血浆相互作用 膜（PM）代表线粒体利用的一种形式，其在线粒体膜的那些部分中赋予优势。 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 这种相互作用的意义及其遗传基础。为此，我们将采用 结构-功能方法，利用果蝇的小尺寸和遗传工具。在目标1中， 用连续阻滞面扫描电镜观察神经元类型， 区域服务的企业-PM互动。在Aim 2中，我们将使用一种新的超分辨率形式 研究这些相互作用的形成和分解，以及 突触前生理学和神经传递。在目标3中，我们将研究一组选定的 基因被鉴定为候选人的作用，在pneumal-PM相互作用。其意义 建议在于其揭示新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。

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.