Abstract
Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAAs) are essential amino acids needed for anabolic processes, 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 in rodents. We found that mitochondrial BCAA oxidation in brown adipose tissue (BAT) is significantly enhanced during fever in response to the pyrogenic mediator prostaglandin E2 (PGE2) and psychological stress in mice and rats. Genetic deletion of MBC in a BAT-specific manner blunts mitochondrial BCAA oxidation and non-shivering thermogenesis following intracerebroventricular PGE2 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.
Highlights
Eukaryotic cells utilize metabolites in distinct organelles during adaptation to stress
Leucine is a branched-chain amino acid (BCAA) that is essential amino acid needed for anabolic processes, including protein synthesis and nutrition sensing via mTOR activation; leucine is imported into the mitochondrial matrix for catabolic processes in metabolic organs, such as skeletal muscle and brown adipose tissue (BAT) upon exercise and cold adaptation, respectively (Neinast et al, 2019a, Lynch and Adams, 2014)
prostaglandin E2 (PGE2) is a well-established pyrogenic mediator that binds to the EP3 subtype of its receptor in the preoptic area (POA) and triggers the pyrogenic circuit mechanism for the stimulation of sympathetic nerve activity likely by inhibiting thermoregulatory warmsensitive POA neurons (Nakamura and Morrison, 2011, Nakamura, 2011)
Summary
Eukaryotic cells utilize metabolites in distinct organelles during adaptation to stress. Such adaptive mechanisms provide another layer of flexibility in metabolite utilization, a.k.a., metabolic flexibility, thereby allowing for robust adaptive fitness to stress. Leucine is a branched-chain amino acid (BCAA) that is essential amino acid needed for anabolic processes, including protein synthesis and nutrition sensing via mTOR activation; leucine is imported into the mitochondrial matrix for catabolic processes in metabolic organs, such as skeletal muscle and brown adipose tissue (BAT) upon exercise and cold adaptation, respectively (Neinast et al, 2019a, Lynch and Adams, 2014). The factors controlling the subcellular metabolite utilization, e.g., the anabolic vs catabolic responses to BCAA, during stress adaptation remains poorly understood. Mitochondrial pyruvate carrier proteins (MPC1 and MPC2) are responsible for importing pyruvate into the matrix (Bricker et al, 2012, Herzig et al, 2012). Loss of MPC leads to reduced pyruvate oxidation, thereby shifting cellular metabolism toward glycolysis, a.k.a., the Warburg effect, whereas ectopic expression of MPC1/2 promotes mitochondrial pyruvate oxidation via pyruvate dehydrogenase (PDH) (Schell et al, 2014, Vacanti et al, 2014)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
