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Mitochondrial ROS-derived PTEN oxidation activates PI3K pathway for mTOR-induced myogenic autophagy

Abstract

Muscle differentiation is a crucial process controlling muscle development and homeostasis. Mitochondrial reactive oxygen species (mtROS) rapidly increase and function as critical cell signaling intermediates during the muscle differentiation. However, it has not yet been elucidated how they control myogenic signaling. Autophagy, a lysosome-mediated degradation pathway, is importantly recognized as intracellular remodeling mechanism of cellular organelles during muscle differentiation. Here, we demonstrated that the mtROS stimulated phosphatidylinositol 3 kinase/AKT/mammalian target of rapamycin (mTOR) cascade, and the activated mTORC1 subsequently induced autophagic signaling via phosphorylation of uncoordinated-51-like kinase 1 (ULK1) at serine 317 and upregulation of Atg proteins to prompt muscle differentiation. Treatment with MitoQ or rapamycin impaired both phosphorylation of ULK1 and expression of Atg proteins. Therefore, we propose a novel regulatory paradigm in which mtROS are required to initiate autophagic reconstruction of cellular organization through mTOR activation in muscle differentiation.

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Acknowledgements

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2016R1D1A1B03933763 to TGC, and NRF-2011-0030072, NRF-2017R1A2B2007870, and NRF-2018R1A6A1A03025124 to SSK).

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Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to Sung Soo Kim.

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