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

  1. Takeshi Yoneshiro
  2. Naoya Kataoka
  3. Jacquelyn M Walejko
  4. Kenji Ikeda
  5. Zachary Brown
  6. Momoko Yoneshiro
  7. Scott B Crown
  8. Tsuyoshi Osawa
  9. Juro Sakai
  10. Robert W McGarrah
  11. Phillip J White
  12. Kazuhiro Nakamura
  13. Shingo Kajimura  Is a corresponding author
  1. University of Tokyo, Japan
  2. Nagoya University Graduate School of Medicine, Japan
  3. Duke University School of Medicine, United States
  4. Tokyo Medical and Dental University, Japan
  5. University of California, San Francisco, United States
  6. The University of Tokyo, Japan
  7. 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.

The following previously published data sets were used

Article and author information

Author details

  1. Takeshi Yoneshiro

    Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Naoya Kataoka

    Department of Integrative Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. 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.
  4. 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.
  5. Zachary Brown

    Diabetes Center, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Momoko Yoneshiro

    Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. Kazuhiro Nakamura

    Department of Integrative Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
    Competing interests
    The authors declare that no competing interests exist.
  13. 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.
    ORCID icon "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.

Reviewing Editor

  1. Ralph J DeBerardinis, UT Southwestern Medical Center, United States

Publication history

  1. Received: January 25, 2021
  2. Accepted: May 2, 2021
  3. Accepted Manuscript published: May 4, 2021 (version 1)
  4. Version of Record published: May 20, 2021 (version 2)

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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  1. Takeshi Yoneshiro
  2. Naoya Kataoka
  3. Jacquelyn M Walejko
  4. Kenji Ikeda
  5. Zachary Brown
  6. Momoko Yoneshiro
  7. Scott B Crown
  8. Tsuyoshi Osawa
  9. Juro Sakai
  10. Robert W McGarrah
  11. Phillip J White
  12. Kazuhiro Nakamura
  13. Shingo Kajimura
(2021)
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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