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，它可以成为推动表型的分子、代谢和生理方面的主要动力，因此，恢复细胞内平衡的调节对生物体的生存至关重要。线粒体是这些调节的中心，因为它们整合了多条途径，并执行生命最重要的生物功能之一--三磷酸腺苷的产生。具体地说，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，例如运输脂肪酸的肉毒碱穿梭载体和运输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输系统(ETS)提供电子，从而允许通过氧化磷酸化过程产生ATP。ETS由几个著名的酶复合体(复合体I至V)组成，但也由其他较少被研究的电子供给器组成，如甘油-3-磷酸穿梭和电子转移黄素蛋白。在营养胁迫过程中，涉及雷帕霉素、AMPK、Sirtuin-1和胰岛素等多种效应因子的信号通路可以激活和调节线粒体新陈代谢。另一种应激反应，线粒体未折叠蛋白反应，也可以由轻微的线粒体功能障碍触发，这可能是由营养胁迫引起的。然而，细胞如何激活这些不同的分子反应取决于应激的类型和强度，这些反应在多大程度上相互作用来微调线粒体新陈代谢，哪些ETS成分是环境挑战期间调节的主要目标，以及这些细胞在表型水平上的调节结果是根本重要的，但在很大程度上仍未解决的问题。 我的研究计划将通过控制饮食组成和可用性，以及通过使用暴露在不同饮食挑战中的几种基因型的黑腹果蝇，通过损害线粒体转运体和电子进入ETS来解决这些问题。具体地说，我将： -描述不同的线粒体途径和功能如何在环境应激期间相互作用，以促进代偿反应。 -确定线粒体底物转运体和不同的ETS补给贡献者对这些代偿反应的影响。 这项研究计划将整合生物体在营养波动期间发生的代谢、分子和生理反应，因此将阐明允许代谢灵活性的机制，并最终使生物体适应环境压力。

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.