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Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity

Author

Listed:
  • Yuki Takakura

    (Graduate School of Pharmaceutical Sciences, Chiba University
    Graduate School of Pharmaceutical Sciences, Chiba University
    RIKEN Center for Integrative Medical Sciences)

  • Moeka Machida

    (Graduate School of Pharmaceutical Sciences, Chiba University
    Graduate School of Pharmaceutical Sciences, Chiba University)

  • Natsumi Terada

    (Graduate School of Pharmaceutical Sciences, Chiba University
    Graduate School of Pharmaceutical Sciences, Chiba University)

  • Yuka Katsumi

    (Graduate School of Pharmaceutical Sciences, Chiba University)

  • Seika Kawamura

    (Graduate School of Pharmaceutical Sciences, Chiba University)

  • Kenta Horie

    (RIKEN Center for Integrative Medical Sciences)

  • Maki Miyauchi

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

  • Tatsuya Ishikawa

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

  • Nobuko Akiyama

    (RIKEN Center for Integrative Medical Sciences)

  • Takao Seki

    (RIKEN Center for Integrative Medical Sciences)

  • Takahisa Miyao

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

  • Mio Hayama

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

  • Rin Endo

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

  • Hiroto Ishii

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

  • Yuya Maruyama

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

  • Naho Hagiwara

    (RIKEN Center for Integrative Medical Sciences)

  • Tetsuya J. Kobayashi

    (The University of Tokyo)

  • Naoto Yamaguchi

    (Graduate School of Pharmaceutical Sciences, Chiba University)

  • Hiroyuki Takano

    (Graduate School of Pharmaceutical Sciences, Chiba University)

  • Taishin Akiyama

    (RIKEN Center for Integrative Medical Sciences
    Yokohama City University)

  • Noritaka Yamaguchi

    (Graduate School of Pharmaceutical Sciences, Chiba University
    Graduate School of Pharmaceutical Sciences, Chiba University
    RIKEN Center for Integrative Medical Sciences)

Abstract

Autophagy is primarily activated by cellular stress, such as starvation or mitochondrial damage. However, stress-independent autophagy is activated by unclear mechanisms in several cell types, such as thymic epithelial cells (TECs). Here we report that the mitochondrial protein, C15ORF48, is a critical inducer of stress-independent autophagy. Mechanistically, C15ORF48 reduces the mitochondrial membrane potential and lowers intracellular ATP levels, thereby activating AMP-activated protein kinase and its downstream Unc-51-like kinase 1. Interestingly, C15ORF48-dependent induction of autophagy upregulates intracellular glutathione levels, promoting cell survival by reducing oxidative stress. Mice deficient in C15orf48 show a reduction in stress-independent autophagy in TECs, but not in typical starvation-induced autophagy in skeletal muscles. Moreover, C15orf48–/– mice develop autoimmunity, which is consistent with the fact that the stress-independent autophagy in TECs is crucial for the thymic self-tolerance. These results suggest that C15ORF48 induces stress-independent autophagy, thereby regulating oxidative stress and self-tolerance.

Suggested Citation

  • Yuki Takakura & Moeka Machida & Natsumi Terada & Yuka Katsumi & Seika Kawamura & Kenta Horie & Maki Miyauchi & Tatsuya Ishikawa & Nobuko Akiyama & Takao Seki & Takahisa Miyao & Mio Hayama & Rin Endo &, 2024. "Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45206-1
    DOI: 10.1038/s41467-024-45206-1
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    References listed on IDEAS

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