Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function
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Chuanyan Zhao1,*, Zhuyun Chen1,*, Jia Qi2, Suyan Duan1, Zhimin Huang1, Chengning Zhang1, Lin Wu1, Ming Zeng1, Bo Zhang1, Ningning Wang1, Huijuan Mao1, Aihua Zhang3,4, Changying Xing1, Yanggang Yuan1
1Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
2Department of Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
3Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China
4Institute of Pediatrics, Nanjing Medical University, Nanjing, China
*These authors are contributed equally to this work
Yanggang Yuan, email: [email protected]
Changying Xing, email: [email protected]
Keywords: Drp1, mitophagy, mitochondrial dysfunction, mitochondrial fission, cisplatin
Received: July 10, 2016 Accepted: February 07, 2017 Published: February 18, 2017
Cisplatin chemotherapy often causes acute kidney injury (AKI) in cancer patients. There is increasing evidence that mitochondrial dysfunction plays an important role in cisplatin-induced nephrotoxicity. Degradation of damaged mitochondria is carried out by mitophagy. Although mitophagy is considered of particular importance in protecting against AKI, little is known of the precise role of mitophagy and its molecular mechanisms during cisplatin-induced nephrotoxicity. Also, evidence that activation of mitophagy improved mitochondrial function is lacking. Furthermore, several evidences have shown that mitochondrial fission coordinates with mitophagy. The aim of this study was to investigate whether activation of mitophagy protects against mitochondrial dysfunction and renal proximal tubular cells injury during cisplatin treatment. The effect of mitochondrial fission on mitophagy was also investigated. In cultured human renal proximal tubular cells, we observed that 3-methyladenine, a pharmacological inhibitor of autophagy, blocked mitophagy and exacerbated cisplatin-induced mitochondrial dysfunction and cells injury. In contrast, autophagy activator rapamycin enhanced mitophagy and protected against the harmful effects of cisplatin on mitochondrial function and cells viability. Suppression of mitochondrial fission by knockdown of its main regulator dynamin-related protein-1 (Drp1) decreased cisplatin-induced mitophagy. Meanwhile, Drp1 suppression protected against cisplatin-induced cells injury by inhibiting mitochondrial dysfunction. Our results provide evidence that Drp1-depedent mitophagy has potential as renoprotective targets for the treatment of cisplatin-induced AKI.
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