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Open AccessArticle

High Levels of ROS Impair Lysosomal Acidity and Autophagy Flux in Glucose-Deprived Fibroblasts by Activating ATM and Erk Pathways

Department of Life Science, University of Seoul, Dongdaemun-gu, Seoulsiripdae-ro 163, Seoul 02504, Korea
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Author to whom correspondence should be addressed.
Biomolecules 2020, 10(5), 761; https://doi.org/10.3390/biom10050761
Received: 31 January 2020 / Revised: 8 May 2020 / Accepted: 10 May 2020 / Published: 13 May 2020
Under glucose deprivation, cells heavily mobilize oxidative phosphorylation to maintain energy homeostasis. This leads to the generation of high levels of ATP, as well as reactive oxygen species (ROS), from mitochondria. In nutrient starvation, autophagy is activated, likely to facilitate resource recycling, but recent studies suggest that autophagy flux is inhibited in cells undergoing glucose deprivation. In this study, we analyzed the status of autophagic flux in glucose-deprived human fibroblasts. Although lysosomes increased in quantity due in part to an increase of biogenesis, a large population of them suffered low acidity in the glucose-deprived cells. Autophagosomes also accumulated due to poor autolysis in these cells. A treatment of antioxidants not only restored lysosomal acidity but also released the flux blockade. The inhibition of ataxia telangiectasia mutated (ATM) serine/threonine kinase, which is activated by ROS, also attenuated the impairment of lysosomal acidity and autophagic flux, suggesting an effect of ROS that might be mediated through ATM activation. In addition, the activity of extracellular signal-regulated kinase (Erk) increased upon glucose deprivation, but this was also compromised by a treatment of antioxidants. Furthermore, the Erk inhibitor treatment also alleviated the failure in lysosomal acidity and autophagic flux. These together indicate that, upon glucose deprivation, cells undergo a failure of autophagy flux through an impairment of lysosomal acidity and that a high-level ROS-induced activation of Erk and ATM is involved in this impairment. View Full-Text
Keywords: ATP; glucose deprivation; autophagy; autophagy flux; ataxia-telangiectasia mutated (ATM); reactive oxygen species (ROS); extracellular-signal-regulated kinase (Erk) ATP; glucose deprivation; autophagy; autophagy flux; ataxia-telangiectasia mutated (ATM); reactive oxygen species (ROS); extracellular-signal-regulated kinase (Erk)
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Song, S.B.; Hwang, E.S. High Levels of ROS Impair Lysosomal Acidity and Autophagy Flux in Glucose-Deprived Fibroblasts by Activating ATM and Erk Pathways. Biomolecules 2020, 10, 761.

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