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

Takakura, Y.; Machida, M.; Terada, N.; Katsumi, Y.; Kawamura, S.; Horie, K.; Miyauchi, M.; Ishikawa, T.; Akiyama, N.; Seki, T.; Miyao, T.; Hayama, M.; Endo, R.; Ishii, H.; Maruyama, Y.; Hagiwara, N.; Kobayashi, T. J.; Yamaguchi, N.; Takano, H.; Akiyama, T.

doi:10.1101/2023.10.17.562644

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bioRxiv · 10.1101/2023.10.17.562644

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

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Abstract

Autophagy is primarily activated by cellular stress, such as starvation or mitochondrial damage. However, stress-independent autophagy is activated by unknown 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 induction of autophagy upregulates intracellular glutathione levels, promoting cell survival by reducing oxidative stress. Mice deficient in C15orf48 showed a reduction in stress-independent autophagy in TECs, but not in typical starvation-induced autophagy in skeletal muscles. Moreover, C15orf48-/- mice developed 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.

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Takakura, Y., Machida, M., Terada, N., Katsumi, Y., Kawamura, S., Horie, K., Miyauchi, M., Ishikawa, T., Akiyama, N., Seki, T., Miyao, T., Hayama, M., Endo, R., Ishii, H., Maruyama, Y., Hagiwara, N., Kobayashi, T. J., Yamaguchi, N., Takano, H., Akiyama, T.. 2023-10-19. Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity. https://doi.org/10.1101/2023.10.17.562644

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