Grant: Discovery Grants Program - Individual

A change in dietary resources is an important environmental parameter that can be a major force drivingmolecular, 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 substratesare 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 bymanipulating 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 onthe mechanisms allowing the metabolic flexibility and ultimately organisms adaptation to environmental stress.