LAUSR

Emerging evidence suggests that brown adipose tissue (BAT) has roles outside of thermogenesis, including acting as a metabolic sink for glucose and fatty acids. Now, Shingo Kajimura and colleagues report that the catabolism of branched-chain amino acids (BCAAs) in BAT is reliant on a newly characterized mitochondrial BCAA transporter, SLC25A44. “The existence of a mitochondrial BCAA transporter has been suggested for over 20 years,” explains Kajimura. “Many cells contain the mitochondria-localized branched-chain aminotransferase, BAT2, which suggests that BCAAs could be transported into the mitochondrial matrix, but whether this is the case or not has been a long-standing mystery.” As BAT exclusively utilizes BCAAs in the mitochondria, the authors felt that BAT would be an ideal discovery tool in the search for a mitochondrial BCAA transporter. To investigate the role of BAT in BCAA uptake, Kajimura and colleagues used genetic mouse models, including BAT-deletion mice (UCP1-Cre x PPARγ) and mice that had the key enzyme for BCAA catabolism, BCKDH, deleted specifically from BAT. “We unexpectedly found that BAT actively uptakes BCAAs and promotes BCAA clearance from the circulation,” explains Kajimura. “In addition, the disruption of BCKDH in BAT impaired BCAA clearance and induced obesity and diabetes mellitus in mice.” Next, Kajimura and colleagues used biochemical techniques and conducted metabolomics in mice and humans to further investigate the role of BAT as a metabolic sink. The team found that in response to cold stimuli, mitochondria within BAT potently uptake BCAAs, which in turn promotes the clearance of BCAAs from the circulation. The uptake of BCAAs into mitochondria was reliant on the mitochondrial BCAA transporter SLC25A44, which is part of the SLC25A family of solute carrier transporter proteins. The authors now want to investigate whether it is possible to enhance the mitochondrial BCAA transport activity. “BCAA oxidation in mitochondria is impaired in individuals with obesity and patients with diabetes mellitus,” concludes Kajimura “The enhancement of mitochondrial BCAA transport activity could be a new therapeutic opportunity for these diseases.”