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

• Published in: Nature communications 2024-02, Vol.15 (1), p.953-19, Article 953
• Main Authors: Takakura, Yuki, Machida, Moeka, Terada, Natsumi, Katsumi, Yuka, Kawamura, Seika, Horie, Kenta, Miyauchi, Maki, Ishikawa, Tatsuya, Akiyama, Nobuko, Seki, Takao, Miyao, Takahisa, Hayama, Mio, Endo, Rin, Ishii, Hiroto, Maruyama, Yuya, Hagiwara, Naho, Kobayashi, Tetsuya J., Yamaguchi, Naoto, Takano, Hiroyuki, Akiyama, Taishin, Yamaguchi, Noritaka
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/31; 13/89; 13/95; 14; 14/19; 49/88; 631/250/1933; 631/250/38; 631/80/39/2346; 64/60; 82/51; AMP-activated protein kinase; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Autoimmunity; Autophagy; Cell survival; Cellular stress response; Epithelial cells; Epithelial Cells - metabolism; Epithelium; Glutathione; Humanities and Social Sciences; Immunological tolerance; Intracellular; Kinases; Membrane potential; Mice; Mitochondria; Mitochondrial Proteins - metabolism; multidisciplinary; Muscles; Oxidative Stress; Proteins; Science; Science (multidisciplinary); Skeletal muscle; Thymus
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45206-1

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. Stress-independent autophagy is less understood than stress-induced autophagy and is important for thymic self-tolerance. Here the authors show that a mitochondrial protein C15ORF48 is important for stress-independent autophagy and alters glutathione metabolism and C15orf48 knockout mice develop autoimmunity and changes to thymic epithelial cells.