Metabolic flexibility via mitochondrial bcaa carrier slc25a44 is required for optimal fever

Takeshi Yoneshiro, Naoya Kataoka, Jacquelyn M. Walejko, Kenji Ikeda, Zachary Brown, Momoko Yoneshiro, Scott B. Crown, Tsuyoshi Osawa, Juro Sakai, Robert W. McGarrah, Phillip J. White, Kazuhiro Nakamura, Shingo Kajimura

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere66865
JournaleLife
Volume10
DOIs
Publication statusPublished - 2021 May
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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