Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever

ABSTRACT Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAA, Valine, Leucine, and Isoleucine) are essential for anabolic processes like protein synthesis, but they are also imported into the mitochondria for catabolic reactions. What controls the distinct subcellular BCAA utilization during stress adaptation is insufficiently understood. The present study reports the role of SLC25A44, a recently identified mitochondrial BCAA carrier (MBC), in the regulation of mitochondrial BCAA catabolism and adaptive response to fever. We found that mitochondrial BCAA oxidation in brown adipose tissue (BAT) is significantly enhanced during fever in response to the pyrogenic mediator prostaglandin E 2 (PGE 2 ) and psychological stress. Genetic deletion of MBC in a BAT-specific manner blunts mitochondrial BCAA oxidation and non-shivering thermogenesis following intracerebroventricular PGE 2 administration. At a cellular level, MBC is required for mitochondrial BCAA deamination as well as the synthesis of mitochondrial amino acids and TCA intermediates. Together, these results illuminate the role of MBC as a determinant of metabolic flexibility to mitochondrial BCAA catabolism and optimal febrile responses. This study also offers an opportunity to control fever by rewiring the subcellular BCAA fate.