Metabolic flexibility during challenging environmental conditions in Drosophila

果蝇在挑战性环境条件下的代谢灵活性

• 批准号: RGPIN-2017-05100
• 负责人: Pichaud, Nicolas
• 金额: $ 2.19万
• 依托单位: Université de Moncton
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=662118
• 关键词: Metabolic; flexibility; during; challenging; environmental

A change in dietary resources is an important environmental parameter that can be a major force driving molecular, metabolic and physiological aspects of phenotype, and adjustments to restore cellular homeostasis are hence fundamental for the survival of organisms. The mitochondria are central to these adjustments as they integrate multiple pathways and perform one of life's most important biological functions, the ATP production. Specifically, the nutrients in the diet are processed by the cell and the resulting substrates are transported inside the mitochondria by rate-limiting carriers such as the carnitine shuttle transporting the fatty acids and the mitochondrial pyruvate carrier which transports pyruvate, the end product of glycolysis. In the mitochondria, the substrates are oxidized to provide electrons to the electron transport system (ETS), allowing the production of ATP via the oxidative phosphorylation process. The ETS is constituted of several well-known enzymatic complexes (complexes I to V), but also of other less investigated electron feeders such as the glycerol-3-phosphate shuttle and the electron transferring flavoprotein. During nutrient stress, signaling pathways involving several effectors such as the target of rapamycin, AMPK, Sirtuin-1 and insulin, have been shown to activate and modulate the mitochondrial metabolism. Another stress response, the mitochondrial unfolded protein response, can also be triggered by mild mitochondrial dysfunctions that might result from nutrient stress. However, how the cell activates these different molecular responses depending on the type and intensity of stress, to which extent these responses interact to fine-tune the mitochondrial metabolism, what ETS components are prime targets for adjustments during environmental challenges, and what are the consequences of these cellular adjustments at the phenotypic level are fundamentally important, yet largely unresolved questions.***My research program will harness these questions by manipulating the diet composition and availability, and by impairing the mitochondrial transporters and the entry of electrons into the ETS using several genotypes of Drosophila melanogaster exposed to different dietary challenges. Specifically, I will:***- Describe how different mitochondrial pathways and functions interact during environmental stress to promote compensatory responses.***- Determine the implication of the mitochondrial substrate transporters and of the different ETS feeding contributors to these compensatory responses.***This research program will integrate the metabolic, molecular and physiological responses that occur in organisms during nutrient fluctuation and will therefore shed light on the mechanisms allowing the metabolic flexibility and ultimately organism's adaptation to environmental stress.

饮食资源的变化是一个重要的环境参数，可以是驱动分子，代谢和生理方面的表型的主要力量，并调整恢复细胞内稳态因此是生物体生存的基础。线粒体是这些调整的核心，因为它们整合了多种途径，并执行生命中最重要的生物功能之一，ATP生产。具体而言，饮食中的营养物质由细胞加工，并且所得底物通过限速载体在线粒体内转运，所述限速载体例如转运脂肪酸的肉毒碱穿梭体和转运丙酮酸（糖酵解的最终产物）的线粒体丙酮酸载体。在线粒体中，底物被氧化以向电子传递系统（ETS）提供电子，从而允许通过氧化磷酸化过程产生ATP。ETS是由几个众所周知的酶复合物（复合物I至V），但也有其他较少研究的电子馈线，如甘油-3-磷酸穿梭和电子转移黄素蛋白。在营养胁迫期间，涉及几种效应物（如雷帕霉素、AMPK、Sirtuin-1和胰岛素的靶标）的信号传导途径已被证明激活和调节线粒体代谢。另一种应激反应，线粒体未折叠蛋白反应，也可以由轻度线粒体功能障碍触发，这可能是由营养应激引起的。然而，细胞如何根据压力的类型和强度激活这些不同的分子反应，这些反应在多大程度上相互作用以微调线粒体代谢，哪些ETS组分是环境挑战期间调整的主要目标，以及这些细胞在表型水平上调整的后果是根本重要的，但在很大程度上尚未解决的问题。我的研究计划将通过操纵饮食组成和可用性来解决这些问题，并通过使用暴露于不同饮食挑战的几种基因型果蝇来损害线粒体转运蛋白和电子进入ETS。具体来说，我将：*-描述不同的线粒体途径和功能如何在环境压力下相互作用，以促进代偿反应。确定线粒体底物转运蛋白和不同的ETS进食贡献者对这些补偿反应的影响。*该研究计划将整合营养波动期间生物体中发生的代谢，分子和生理反应，因此将揭示代谢灵活性和最终生物体适应环境压力的机制。