Metabolic flexibility during challenging environmental conditions in Drosophila

饮食资源的变化是一个重要的环境参数，可以是驱动表型分子、代谢和生理方面的主要力量，因此恢复细胞稳态的调整是生物体生存的基础。线粒体是这些调节的核心，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，即ATP的产生。具体来说，饮食中的营养物质由细胞处理，产生的底物通过限速载体在线粒体内运输，如运送脂肪酸的肉碱穿梭体和运送糖酵解最终产物丙酮酸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由几种众所周知的酶复合物（复合物I到V）组成，但也有其他较少研究的电子供给体，如甘油-3-磷酸穿梭体和电子转移黄蛋白。在营养胁迫过程中，包括雷帕霉素靶点、AMPK、Sirtuin-1和胰岛素等多种效应物在内的信号通路已被证明可以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，也可以由可能由营养应激引起的轻度线粒体功能障碍触发。然而，细胞如何根据应激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，在环境挑战中哪些ETS成分是调整的主要目标，以及这些细胞调整在表型水平上的后果是非常重要的，但在很大程度上尚未解决的问题。

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.