Mitophagy alleviates cisplatin-induced renal tubular epithelial cell ferroptosis through ROS/HO-1/GPX4 axis

• Published in: International journal of biological sciences Vol. 19; no. 4; pp. 1192 - 1210
• Main Authors: Lin, Qisheng, Li, Shu, Jin, Haijiao, Cai, Hong, Zhu, Xuying, Yang, Yuanting, Wu, Jingkui, Qi, Chaojun, Shao, Xinghua, Li, Jialin, Zhang, Kaiqi, Zhou, Wenyan, Zhang, Minfang, Cheng, Jiayi, Gu, Leyi, Mou, Shan, Ni, Zhaohui
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 01-01-2023
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - metabolism; Animals; Cisplatin - adverse effects; Epithelial Cells - metabolism; Ferroptosis; Mice; Mice, Knockout; Mitophagy - genetics; Protein Kinases - metabolism; Reactive Oxygen Species - metabolism; Research Paper; mitophagy; ferroptosis; cisplatin nephrotoxicity; Acute kidney injury
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.80775

Cisplatin is widely recommended in combination for the treatment of tumors, thus inevitably increasing the incidence of cisplatin-induced acute kidney injury. Mitophagy is a type of mitochondrial quality control mechanism that degrades damaged mitochondria and maintains cellular homeostasis. Ferroptosis, a new modality of programmed cell death, is characterized by iron-dependent phospholipid peroxidation and oxidative membrane damage. However, the role of mitophagy in ferroptosis in kidney disease is unclear. Here, we investigated the mechanism underlying both BNIP3-mediated and PINK1-PARK2-mediated mitophagy-induced attenuation of ferroptosis in cisplatin-induced acute kidney injury. The results showed that cisplatin induced mitochondrial injury, ROS release, intracellular iron accumulation, lipid peroxidation and ferroptosis in the kidney, which were aggravated in
, Pink1
or
knockout cisplatin-treated mice. Ferrstatin-1, a synthetic antioxidative ferroptosis inhibitor, rescued iron accumulation, lipid peroxidation and ferroptosis caused by inhibition of mitophagy. Thus, the present study elucidated a novel mechanism by which both BNIP3-mediated and PINK1-PARK2-mediated mitophagy protects against cisplatin-induced renal tubular epithelial cell ferroptosis through the ROS/HO1/GPX4 axis.