Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function.
Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function.
复制标题
Drp1依赖性线粒体自噬通过改善线粒体功能来防止顺铂诱导的肾小管上皮细胞凋亡
DOI：
10.18632/oncotarget.15470
复制
发表时间：
2017-03-28
期刊：
影响因子：
--
通讯作者：
Yuan Y
中科院分区：
文献类型：
--
作者：
Zhao C;Chen Z;Qi J;Duan S;Huang Z;Zhang C;Wu L;Zeng M;Zhang B;Wang N;Mao H;Zhang A;Xing C;Yuan Y
顺铂化疗常引起癌症患者的急性肾损伤（阿基）。越来越多的证据表明，线粒体功能障碍在顺铂诱导的肾毒性中起重要作用。受损线粒体的降解通过线粒体自噬进行。虽然线粒体自噬被认为在预防阿基方面特别重要，但对顺铂诱导的肾毒性期间线粒体自噬的确切作用及其分子机制知之甚少。此外，缺乏激活线粒体自噬改善线粒体功能的证据。此外，一些证据表明，线粒体分裂与线粒体自噬协调。本研究的目的是调查是否激活线粒体自噬保护线粒体功能障碍和肾近端肾小管细胞损伤顺铂治疗。线粒体分裂对线粒体自噬的影响也进行了研究。在培养的人肾近端小管细胞中，我们观察到3-甲基腺嘌呤，一种自噬的药理学抑制剂，阻断线粒体自噬，加剧顺铂诱导的线粒体功能障碍和细胞损伤。相比之下，自噬激活剂雷帕霉素增强线粒体自噬，并防止顺铂对线粒体功能和细胞活力的有害影响。通过敲低线粒体分裂的主要调节因子动力蛋白相关蛋白1（Drp 1）来抑制线粒体分裂，从而降低顺铂诱导的线粒体自噬。同时，抑制Drp 1通过抑制线粒体功能障碍来保护顺铂诱导的细胞损伤。我们的研究结果提供了证据表明，Drp 1依赖性线粒体自噬有可能作为顺铂诱导的阿基治疗的肾保护靶点。
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.
影响因子：
3.7
作者：
Butin-Israeli, Veronika;Uzi, Dotan;Abd-El-Latif, Mahmoud;Pizov, Galina;Eden, Arieh;Haviv, Yosef S.;Oppenheim, Ariella
通讯作者：
Oppenheim, Ariella