Exploring the mitochondrial phosphoproteome during metabolic stress

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Mitochondria convert most of the energy contained in nutrients into ATP, which is required to perform all cellular biochemical processes needing energy. Therefore, the mitochondrial metabolism needs to be tightly regulated to maintain survival of cells during metabolic stress. For instance, the mitochondrial ATP production needs to be maintained during low nutrient availability whereas it must be increased during exercise to match the energetic needs of cells. Kinases emerged recently as important regulators of mitochondrial functions. These enzymes change the properties of proteins by adding a phosphate group. Although we know that several kinases can be localized in mitochondria where they can target different proteins, little is known about their importance in the regulation of the mitochondrial metabolism during challenging metabolic conditions. Interestingly, the activity of kinases can be activated by several sub-products of the metabolism which are affected in such conditions. Since mitochondria are key regulators of these metabolites, kinases localized within mitochondria could represent direct messengers to regulate the mitochondrial metabolism during metabolic stress. The proposed research program aims to determine the importance of mitochondrial phosphorylation events in the adjustment of mitochondrial functions in response to metabolic stress. The first objective of this proposal is to determine how mitochondrial levels of key metabolites (reactive oxygen species, calcium and ATP) modulate the mitochondrial phosphoproteome, whereas the second objective is to determine how the mitochondrial phosphoproteome is modulated during fasting and exercise. The mitochondrial proteins targeted by these events will be identified. Then, the generation of mutant proteins mimicking these phosphorylation events will enable to understand the functional impact of these processes on the mitochondrial metabolism. The third objective is to identify the kinases involved in the phosphorylation processes occurring in response to metabolic stress. Globally, this research program will identify new intra-mitochondrial biochemical cascades enabling the adjustment of metabolism in response to challenging metabolic conditions. Most wild animals face persistent metabolic stress. For instance, such animals can stay long periods without eating and/or have to migrate for long distances. Therefore, this research program will eventually identify new molecular mechanisms impacting the adaptation of a given species to its environmental niche. Since defects in mitochondrial functions can lead to different pathologies, including diabetes, cancer and neurodegenerative diseases, this proposed work will be of high interest for the development of new tools indicative of the "health" status of cells, tissues and entire individuals.