Research Paper Volume 16, Issue 9 pp 7683—7703

Figure 6. Lysosome protects senescent cell from ferroptosis-induced cell death. (A) CQ and LLOMe promote the senescent cell death under RSL3 treatment. Cells were treated with either combination of RSL3 and CQ or LLOMe for 12 h, and then cell viability was determined by CCK-8 assay. P-values were calculated by two-way ANOVA analysis, ^*P < 0.05. Data represented as mean ± SD. And three independent biological experiment repeats have been performed. (B) A schematic model for cellular response to iron accumulation in senescent cells. In senescent cells, both the two-iron importer TfR1 and DMT1 expression decreases, probably due to feedback repression of iron accumulation. And iron exporter FPN1 also decreases to reduce the iron efflux from cells. Subsequently the accumulated intracellular Fe²⁺ is bound by the ferritin protein nanocages, and transferred into lysosomes via NCOA4-mediated ferritinophagy. Besides, the number of lysosomes increases, and their size are enlarged in senescent cells, which provides enough space to store the excessive iron. Once the structures and/or functions of lysosome of senescent cells are broken by CQ or LLOMe, the toxic contents of lysosomes would be released, including the labile Fe²⁺ and others, which leads to ferroptosis-induced cell death.