PROJECT SUMMARY The main objective of this Maximizing Investigators' Research Award (MIRA) is to provide new mechanistic insight regarding the metabolic stress response to burn trauma. Specifically, the overarching goal of this research program is to elucidate the role of the mitochondrion in burn-induced hypermetabolism and metabolic dysfunction. Burns are a leading cause of non-fatal trauma in the United States. Today, even the most severe burns are survivable. However, burn survivors endure a protracted recovery, where restoration of function and quality of life are not readily achieved. Accordingly, there is a pressing need for new strategies that reduce morbidity and hasten the recovery of burn survivors. Recent data have implicated mitochondria as mediators of the metabolic stress response to burn trauma. Indeed, altered bioenergetics are thought underlay the hypermetabolic response to burns, and may contribute to burn-induced insulin resistance, altered lipid metabolism and muscle wasting. Further, mitochondrial stress appears to impact cellular homeostasis post burn through the formation of oxygen radicals, and may contribute to the systemic inflammatory response to burns by releasing fragments of mitochondrial DNA (mtDNA) into the circulation. This MIRA will support the development of innovative rodent models of isotopically labeled adipose tissue and skeletal muscle. These models will be leveraged to trace the turnover, redistribution and oxidation of specific substrates in response to burn injury. By combining these novel models with deuterium oxide dosing in vivo, we will generate important data regarding synthesis rates of key mitochondrial proteins in multiple tissues in response to burn trauma. By dovetailing measurements of substrate flux and mitochondrial carrier protein turnover with direct measures of mitochondrial respiratory function, proton leak, membrane potential and superoxide formation, we will elucidate the mechanistic basis of altered bioenergetics and metabolism in response to burn injury. In addition, the utility of ambient temperature, protonophores and mitochondrial targeted antioxidants as strategies to restore bioenergetics and metabolic function post burn will also rigorously tested. Furthermore, blood and tissue samples collected from burn patients will be used to validate preclinical data and to probe the role of mtDNA in the systemic inflammatory response to burn injury. By bettering our mechanistic understanding of the metabolic stress response to burns this research program will contribute new knowledge that may be leveraged to lessen the suffering and promote the recovery of burn survivors. Moreover, since hypermetabolism is present in other forms critical illness, the new information generated by this research program may have broader scientific and clinical impact.