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.

Cellular state determines the multimodal signaling response of single cells

“…In contrast, only the variation in pMTOR not explained by pERK is associated positively with variability in HSP60 (respective partial correlations: -0.14 and 0.49). This shows that pERK senses more strongly the abundance of early endosomes in individual cells than pMTOR, while pMTOR senses more strongly the abundance of mitochondria, in agreement with well-known respective connections between these organelles and signaling nodes 35,36,39,40 .…”

“…To further explore the cellular state properties that have the strongest unique impact on each response node, we started with the response markers pERK and pMTOR, which are well-characterized kinases that have been linked to different properties of the cellular state 35,36,39,40 . Plotting their single-cell abundances after 5 min of exposure to 100ng/ml EGF reveals strong correlation 0.82 .…”

Molecular hydrogen regulates PTEN‐AKT‐mTOR signaling via ROS to alleviate peritoneal dialysis‐related peritoneal fibrosis

“…Studies have shown that ROS negatively regulates PTEN activity . PTEN inhibits PI3K/AKT/mTOR pathway by degrading PIP3 .…”

“…33 Studies have shown that ROS negatively regulates PTEN activity. 34 PTEN inhibits PI3K/AKT/mTOR pathway by degrading PIP3. 35 Our results suggest that upregulation of PTEN expression inhibits activation of PI3K/ AKT/mTOR induced by ROS.…”

Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

“…Macroautophagy, hereafter termed autophagy, is a highly conserved intracellular catabolic pathway in which cytoplasmic constituents are engulfed by double‐membrane vesicles and subsequently delivered to lysosomes for degradation (Cho et al ., ; Denton et al ., ; Fu et al ., ; Galluzzi et al ., ; Goiran et al ., ; Kim et al ., ; Lindqvist et al ., ). Under homeostatic conditions, basal levels of autophagy are required to remove misfolded or aggregated proteins and damaged organelles, such as mitochondria, endoplasmic reticulum (ER), and peroxisomes.…”