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

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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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Article and author information

Author details

Takeshi Yoneshiro

Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Naoya Kataoka

Department of Integrative Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Competing interests
The authors declare that no competing interests exist.
Jacquelyn M Walejko

Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, United States

Competing interests
The authors declare that no competing interests exist.
Kenji Ikeda

Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Zachary Brown

Diabetes Center, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Momoko Yoneshiro

Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Scott B Crown

Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, United States

Competing interests
The authors declare that no competing interests exist.
Tsuyoshi Osawa

Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Juro Sakai

Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Robert W McGarrah

Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, United States

Competing interests
The authors declare that no competing interests exist.
Phillip J White

Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, United States

Competing interests
The authors declare that no competing interests exist.
Kazuhiro Nakamura

Department of Integrative Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Competing interests
The authors declare that no competing interests exist.
Shingo Kajimura

Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Boston, United States

For correspondence
skajimur@bidmc.harvard.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0672-5910

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

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.