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

eLife

Momoko Yoneshiro¹  Naoya Kataoka²  Kazuhiro Nakamura³  Jacquelyn M Walejko⁴  Takeshi Yoneshiro⁵  Zachary Brown⁵  Scott B Crown⁵  Tsuyoshi Osawa⁵  Robert W McGarrah⁶  Phillip J White⁷  Shingo Kajimura⁸  Kenji Ikeda⁸  Juro Sakai⁸ 

[1] Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan;Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan;Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan;Department of Integrative Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan;Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States;Division of Integrative Nutriomics and Oncology, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan;Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan;Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, United States;

关键词: adaptation;    metabolism;    brown adipose tissue;    fever;    mitochondria;    amino acid;   

DOI  :  10.7554/eLife.66865

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown