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

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, Hiroto Ishii, Yuya Maruyama, Naho Hagiwara, Tetsuya J. Kobayashi, Naoto Yamaguchi, Hiroyuki Takano, Taishin Akiyama () and Noritaka Yamaguchi ()
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Yuki Takakura: Graduate School of Pharmaceutical Sciences, Chiba University
Moeka Machida: Graduate School of Pharmaceutical Sciences, Chiba University
Natsumi Terada: 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
Tatsuya Ishikawa: RIKEN Center for Integrative Medical Sciences
Nobuko Akiyama: RIKEN Center for Integrative Medical Sciences
Takao Seki: RIKEN Center for Integrative Medical Sciences
Takahisa Miyao: RIKEN Center for Integrative Medical Sciences
Mio Hayama: RIKEN Center for Integrative Medical Sciences
Rin Endo: RIKEN Center for Integrative Medical Sciences
Hiroto Ishii: RIKEN Center for Integrative Medical Sciences
Yuya Maruyama: RIKEN Center for Integrative Medical Sciences
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
Noritaka Yamaguchi: Graduate School of Pharmaceutical Sciences, Chiba University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45206-1

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