Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever
- University of Tokyo, Japan
- Nagoya University Graduate School of Medicine, Japan
- Duke University School of Medicine, United States
- Tokyo Medical and Dental University, Japan
- University of California, San Francisco, United States
- The University of Tokyo, Japan
- Beth Israel Deaconess Medical Center, United States
Abstract
Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAA) 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.
Data availability
All data generated or analyzed during this study are included in the manuscript as source data files.
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Expression data from exposure of BAT and WAT at 6 and 28 degrees CNCBI Gene Expression Omnibus, GSE51080.
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BioGPS: an extensible and customizable portal for querying and organizing gene annotation resourcesBioGPS, GeneAtlas MOE430, gcrma.
Article and author information
Author details
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK097441)
- Shingo Kajimura
MEXT KAKENHI (15H05932,15K21744)
- Naoya Kataoka
MEXT KAKENHI (20H03418)
- Naoya Kataoka
MEXT KAKENHI (19K06954)
- Kazuhiro Nakamura
AMED (JP21gm5010002s0305)
- Kazuhiro Nakamura
JST Moonshot R&D (JPMJMS2023)
- Kazuhiro Nakamura
National Institute of Diabetes and Digestive and Kidney Diseases (DK126160)
- Shingo Kajimura
National Institute of Diabetes and Digestive and Kidney Diseases (DK125281)
- Shingo Kajimura
National Institute of Diabetes and Digestive and Kidney Diseases (DK127575)
- Shingo Kajimura
The Edward Mallinckrodt, Jr. Foundation
- Shingo Kajimura
National Heart and Lung Institute (5K08HL13527)
- Robert W McGarrah
National Heart and Lung Institute (F32HL137398)
- Scott B Crown
American Diabetes Association (1-16-INI-17)
- Phillip J White
MEXT KAKENHI (19K06954)
- Kazuhiro Nakamura
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All the animal experiments were performed following the guidelines by the UCSF Institutional Animal Care and Use Committee or by the Nagoya University Animal Experiment Committee. The protocols were approved by the committees by the Committee on the Ethics of Animal Experiments of UCSF (AN165833) and Nagoya University. All surgery was performed under anesthesia, and every effort was made to minimize suffering.
Copyright
© 2021, Yoneshiro et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever
eLife 10:e66865.
https://doi.org/10.7554/eLife.66865
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