Midgut mitochondrial function as a driver of resistance and fitness in mosquitoes

项目摘要 在蚊子和模型无脊椎动物中，中肠是胰岛素/胰岛素生长因子的中心。 信令(IIS)。IIS从线虫到哺乳动物的作用很大程度上是通过线粒体来调节的 动力学和活性，定义为线粒体生物发生、生物能量学和损伤清除 线粒体通过有丝分裂。在无脊椎动物和哺乳动物中，依赖IIS的线粒体动力学 线粒体代谢调节一系列重要的生理功能，包括上皮屏障 完整性、干细胞维持和分化、繁殖、寿命和免疫力，表明这一点 在生物有机体中，监管是基本的。在果蝇和秀丽线虫体内，组织-- 线粒体功能的特定变化有助于器官间信号网络，而该网络是这些信号网络的基础 基本的生理过程。尤其是果蝇的肠道和线虫肠道、组织细腻 对压力敏感，通过局部线粒体变化密切参与器官间的通讯 会改变全身线粒体的功能。鉴于这种生物保护，我们的首要目标是广泛地 扩大我们对线粒体作为食血昆虫生理主要调节因子的理解 医学上的重要性。基于我们自己的数据以及来自文献和模型生物的重要数据，我们 假设斯氏按蚊和埃及按蚊中肠线粒体的变化控制 局部的中肠健康，这一信息被系统地传达，以控制线粒体功能和 其他组织的健康状况。此外，我们假设生命史在抵抗感染、长寿 斯氏按蚊和埃及按蚊的繁殖基本上是由中肠局部控制的 由线粒体器官间信号系统协调。我们将从三个具体方面来检验这些假说 目标。在目标1中，我们将定义中肠线粒体对中肠健康的控制通过产生 转基因斯氏艾美耳球虫和埃及艾美耳球虫，过表达调控线粒体生物发生的基因产物， 电子传递链蛋白水平和活性、线粒体融合和功能以及线粒体质量 通过有丝分裂控制。在目标2中，我们将使用在目标1中培育的转基因蚊子来确定 中肠线粒体对全身线粒体活动以及脂肪体、飞行肌肉和脑组织的控制 健康。在目标3中，我们将使用转基因蚊子来识别线粒体信号网络 协调控制寿命、繁殖和对病原体感染的抵抗力。这些表型是 表现为生活史的权衡，我们假设从根本上说是由线粒体控制的。由 在这些研究结束后，我们将了解中肠线粒体功能如何影响局部中肠健康和 控制器官间信号，以调节和协调对载体能力至关重要的生活史特征。

Project Summary In mosquitoes and model invertebrates, the midgut functions as a center for insulin/insulin growth factor signaling (IIS). The effects of IIS from nematodes to mammals are largely mediated through mitochondrial dynamics and activity, defined as mitochondrial biogenesis, bioenergetics, and clearance of damaged mitochondria through mitophagy. In both invertebrates and mammals, IIS-dependent mitochondrial dynamics and mitochondrial metabolism regulate a wide range of important physiologies, including epithelial barrier integrity, stem cell maintenance and differentiation, reproduction, longevity and immunity, indicating that this regulation is fundamental in living organisms. In Drosophila melanogaster and Caenorhabditis elegans, tissue- specific changes in mitochondrial function contribute to an interorgan signaling network that underlies these essential physiological processes. In particular, the fruit fly gut and nematode intestine, tissues exquisitely sensitive to stress, are intimately involved in organ-to-organ communication via local mitochondrial changes that alter systemic mitochondrial function. Given this biological conservation, our overarching goal is to broadly expand our understanding of mitochondria as master regulators of physiology in hematophagous insects of medical importance. Based on our own data and significant data from the literature and model organisms, we hypothesize that changes in the midgut mitochondria of the mosquitoes A. stephensi and A. aegypti control midgut health locally and this information is communicated systemically to control mitochondrial function and health of other tissues. Further, we hypothesize that life history trade-offs in resistance to infection, longevity and reproduction in A. stephensi and A. aegypti are fundamentally controlled locally by the midgut and coordinated systemically by mitochondrial interorgan signaling. We will test these hypotheses in three Specific Aims. In Aim 1, we will define midgut mitochondrial control of midgut health through the generation of transgenic A. stephensi and A. aegypti that overexpress gene products regulating mitochondrial biogenesis, electron transport chain protein levels and activity, mitochondrial fusion and function, and mitochondrial quality control through mitophagy. In Aim 2, we will use the transgenic mosquitoes developed in Aim 1 to define midgut mitochondrial control of systemic mitochondrial activity and fat body, flight muscle, and brain tissue health. And in Aim 3, we will use our transgenic mosquitoes to identify the networks of mitochondrial signaling that coordinately control longevity, reproduction, and resistance to pathogen infection. These phenotypes are manifested as life history trade-offs that we hypothesize are fundamentally controlled by mitochondria. By the end of these studies, we will understand how midgut mitochondrial function affects local midgut health and controls interorgan signaling to regulate and coordinate life history traits critical to vectorial capacity.