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

被引:49
作者
Bao, Lijuan [1 ]
Zhao, Caijun [1 ]
Feng, Lianjun [1 ]
Zhao, Yihong [1 ]
Duan, Shiyu [1 ]
Qiu, Min [1 ]
Wu, Keyi [1 ]
Zhang, Naisheng [1 ]
Hu, Xiaoyu [1 ]
Fu, Yunhe [1 ]
机构
[1] Jilin Univ, Coll Vet Med, Dept Clin Vet Med, Changchun 130062, Jilin, Peoples R China
基金
中国国家自然科学基金;
关键词
Ferroptosis; Ferritinophagy; Autophagy; BPA; Renal tubular; ENDOPLASMIC-RETICULUM STRESS; AUTOPHAGY; DEATH; PROTECTS; EXPOSURE; BPA;
D O I
10.1016/j.fct.2022.112909
中图分类号
TS2 [食品工业];
学科分类号
0832 ;
摘要
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.
引用
收藏
页数:12
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