Identifying and characterizing pathways of amino acid signaling and metabolism

Amino acids, particularly branched-chain amino acids (BCAA) such as leucine, isoleucine, and valine, are mostly used for manufacturing proteins for growth but are also used for generating energy within the powerhouse of the cells (mitochondria). Once inside the cell, BCAA is converted to branch chain alpha ketoacids (BCKA), which are then able to enter the mitochondria for use in the energy generation process. In the previous NSERC funding period, using established methods for analyzing BCAA breakdown products we discovered that BCKA disrupts insulin action thereby hijacking and remodeling cellular metabolism and function. Despite systemic and intracellular presence of BCKA their impact on cellular metabolism, growth and function remains unexplored. In the next NSERC funding period using cell biology, genetics and whole-body approaches we will address two over-arching questions. 1) If/how cellular BCKA exerts control on insulin action and remodel metabolism. 2) If/how BCKA communicates to the cell to dictate cell's ability to synthesize proteins and regulate growth and survival. We will investigate regulation of BCKA entry and exit from cells, how BCKA perturb insulin action, how BCKA targets mitochondrial well being, if BCKA competes with other nutrients for consumption by the cell for energy and which pathways regulate this process of nutrient competition. We will examine whether BCKA chemically or structurally modifies mitochondria to govern metabolism, respiration and survival. We will identify and characterize genes and proteins that are triggered by BCKA and ascertain if/how BCKA signals within the cell to modulate protein turnover and synthesis pathways. This research will provide undergraduate and graduate HQP in my laboratory with training in cell and molecular biology methodologies and in technologies for detection and targeting of molecular players involved in amino acid metabolism. Clarifying molecular networks of cellular BCKA signaling, metabolism and physiology will directly contribute to expanding our knowledge of amino acid biology with long-lasting impacts in the field of energy metabolism, food science and human nutrition benefitting Canadian discovery science, education and innovation.