Organelles are increasingly recognized as central hubs that integrate oxidative and metabolic stress signals to regulate cell survival pathways. Moderate increases in intracellular stress can trigger autophagy as a protective mechanism, whereas nutrient deprivation engages a pro-autophagic program. Here, we investigated how modulating organelle ion exchange influences these stress responses. We subjected cultured cells to oxidative stress (hydroperoxide), nutrient starvation, or both, while pharmacologically manipulating lysosomal ion exchange by altering lysosomal pH and Ca 2+ flux. We then monitored AKT/mTORC1 phosphorylation and the autophagy marker LC3-II. Exposure to either stress alone caused marked activation of intracellular signaling (increased AKT phosphorylation) together with robust autophagosome formation (elevated LC3 lipidation), consistent with a protective autophagy program. Mechanistically, reactive oxygen species (ROS) triggered organelle Ca 2+ efflux, linking lysosomal ion homeostasis to autophagy induction and further promoting autophagic flux. Under combined oxidative and nutrient stress, these effects were amplified: we observed additive changes in intracellular signaling and heightened LC3-II accumulation, suggesting that ROS generated under these conditions synergize with exogenous oxidants to maximize autophagy. Collectively, our findings indicate that maintaining organelle ion homeostasis helps cells cope with oxidative and metabolic stress by fine-tuning AKT/mTORC1 signaling and autophagic activity. This work highlights a mechanistic link between lysosomal ion exchange and stress resilience, suggesting that targeting organelle ion channels could be a promising strategy to boost cellular stress resistance. This research was supported by Korea Basic Science Institute (National research Facilities and Equipment Center) grant funded by Ministry of Science and ICT (RS-2025-00555198) and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2025-00553251).
Oh et al. (Sun,) studied this question.