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

eLife

Naoya Kataoka¹  Kazuhiro Nakamura¹  Momoko Yoneshiro²  Zachary Brown²  Kenji Ikeda³  Shingo Kajimura⁴  Takeshi Yoneshiro⁵  Tsuyoshi Osawa⁶  Juro Sakai⁷  Jacquelyn M Walejko⁸  Scott B Crown⁸  Robert W McGarrah⁹  Phillip J White^1,10 

[1] 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;Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States;Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan;Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States;Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Durham, United States;Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States;Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan;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;Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan;Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, United States;Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, United States;Department of Medicine, Division of Cardiology, Duke University School of Medicine, Durham, United States;Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, United States;Department of Medicine, Division of EndocrinologyMetabolism and Nutrition, Duke University School of Medicine, Durham, United States;

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

DOI  :  10.7554/eLife.66865

来源: eLife Sciences Publications, Ltd

【 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】

CC BY