Ferritinophagy is involved in Bisphenol A-induced ferroptosis of renal tubular epithelial cells through the activation of the AMPK-mTOR-ULK1 pathway

Bisphenol A (BPA) is a common environmental contaminant, whose exposure is associated with the progression of various kidney diseases. BPA exposure has turned out to be associated with cytotoxicity to renal tubular epithelial cells, but its underlying mechanism remains unknown. Herein, we found that BPA induced ferroptosis in kidney and renal tubular epithelial cells, as showed by increased intracellular iron accumulation, lipid per oxidation and cells death upon BPA exposure. Additionally, utilization of ferrostatin-1 and desferrioxamine, typical ferroptosis inhibitors, can fundamentally diminish cells death. Intriguingly, we discovered that autophagy inhibitor chloroquine can shield renal tubular epithelial cells from BPA-caused ferroptosis. Furthermore, we found that ferritinophagy, a phenomenon that degradation of ferritin and inducing subsequent iron overload, occurred after BPA exposure and excessive iron promoted ferroptosis through Fenton reaction. We next demonstrated that BPA activated the AMPK-mTOR-ULK1 signaling pathway. In turn, AMPK, mTOR, and ULK1 knockdown dramatically mitigated BPA-induced TCMK-1 cells death, and decreased MDA and LC3 levels, but increased FTH protein content. These results indicate that activation of the AMPK-mTOR-ULK1 signaling is involved in BPA-induced ferritinophagy. In conclusion, renal dysfunction and renal tubular epithelial damage induced by BPA are linked to ferroptosis, which depends on the activation of ferritinophagy through AMPKmTOR-ULK1 axis.

Automated summary

Research has shown that BPA exposure induces ferroptosis in the kidney and renal tubular epithelial cells, leading to renal dysfunction and cell damage. This process involves the activation of ferritinophagy through the AMPK-mTOR-ULK1 axis.