Artesunate-induced mitophagy alters cellular redox status.
Artesunate-induced mitophagy alters cellular redox status.
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青蒿琥酯诱导的线粒体自噬改变细胞氧化还原状态
DOI：
10.1016/j.redox.2018.07.025
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发表时间：
2018-10
期刊：
影响因子：
11.4
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Zhang J;Sun X;Wang L;Wong YK;Lee YM;Zhou C;Wu G;Zhao T;Yang L;Lu L;Zhong J;Huang D;Wang J
青蒿琥酯（ART）是一种具有显著抗癌特性的突出抗疟疾药物。我们以前的研究表明，ART增强溶酶体功能和铁蛋白降解，这是其抗癌特性所必需的。靶向线粒体的ART也显着提高了其疗效，但ART对线粒体自噬的影响，这是一种促进去除受损线粒体的重要细胞途径，仍然未知。在此，我们首次观察到ART主要定位于线粒体，其探针标记揭示其与大量线粒体蛋白结合并引起线粒体分裂。第二，我们发现ART治疗导致自噬诱导和线粒体蛋白的减少。当自噬被抑制时，线粒体蛋白质的减少可以逆转，表明线粒体蛋白质的降解是通过自噬进行的。第三，我们的研究结果表明，ART处理稳定了线粒体上PTEN诱导的推定激酶1（PINK 1）的全长形式，并激活了PINK 1依赖性途径。这又导致帕金，隔离体1（SQSTM 1），泛素和微管相关蛋白1A/1B轻链3（LC 3）的线粒体和线粒体自噬达到高潮。当PINK 1被敲低时，ART诱导的线粒体自噬被显著抑制。最后，我们研究了ART对线粒体功能的影响，发现PINK 1的敲低改变了ART处理细胞的细胞氧化还原状态，伴随着谷胱甘肽（GSH）的显着减少和线粒体活性氧化物质（mROS）和细胞乳酸水平的增加。此外，PINK 1的敲低导致线粒体去极化的显著增加和ART引起的更多细胞凋亡，表明线粒体自噬保护免于ART诱导的细胞死亡。总之，我们的研究结果揭示了ART通过PINK 1依赖性途径诱导细胞保护性线粒体自噬的分子机制，表明线粒体自噬抑制可以增强ART的抗癌活性。ART与许多线粒体蛋白结合并引起线粒体分裂。ART治疗导致自噬诱导和线粒体蛋白的减少。当PINK 1被敲低时，ART诱导的线粒体自噬被显著抑制。PINK 1的敲低改变ART处理的细胞中的细胞氧化还原状态。ART通过PINK 1依赖性途径和线粒体自噬诱导线粒体自噬。
Artesunate (ART) is a prominent anti-malarial with significant anti-cancer properties. Our previous studies showed that ART enhances lysosomal function and ferritin degradation, which was necessary for its anti-cancer properties. ART targeting to mitochondria also significantly improved its efficacy, but the effect of ART on mitophagy, an important cellular pathway that facilitates the removal of damaged mitochondria, remains unknown. Here, we first observed that ART mainly localizes in the mitochondria and its probe labeling revealed that it binds to a large number of mitochondrial proteins and causes mitochondrial fission. Second, we found that ART treatment leads to autophagy induction and the decrease of mitochondrial proteins. When autophagy is inhibited, the decrease of mitochondrial proteins could be reversed, indicating that the degradation of mitochondrial proteins is through mitophagy. Third, our results showed that ART treatment stabilizes the full-length form of PTEN induced putative kinase 1 (PINK1) on the mitochondria and activates the PINK1-dependent pathway. This in turn leads to the recruitment of Parkin, sequestosome 1 (SQSTM1), ubiquitin and microtubule-associated proteins 1A/1B light chain 3 (LC3) to the mitochondria and culminates in mitophagy. When PINK1 is knocked down, ART-induced mitophagy is markedly suppressed. Finally, we investigated the effect of mitophagy by ART on mitochondrial functions and found that knockdown of PINK1 alters the cellular redox status in ART-treated cells, which is accompanied with a significant decrease in glutathione (GSH) and increase in mitochondrial reactive oxidative species (mROS) and cellular lactate levels. Additionally, knockdown of PINK1 leads to a significant increase of mitochondrial depolarization and more cell apoptosis by ART, suggesting that mitophagy protects from ART-induced cell death. Taken together, our findings reveal the molecular mechanism that ART induces cytoprotective mitophagy through the PINK1-dependent pathway, suggesting that mitophagy inhibition could enhance the anti-cancer activity of ART. ART binds to many mitochondrial proteins and causes mitochondrial fission. ART treatment leads to autophagy induction and the decrease of mitochondrial proteins. When PINK1is knocked down, ART-induced mitophagy is markedly suppressed. Knockdown of PINK1 alters the cellular redox status in ART-treated cells. ART induces mitophagy through the PINK1-dependent pathway and mitophagy.
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DOI：
10.1083/jcb.201008084
发表时间：
2010-11-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jin SM;Lazarou M;Wang C;Kane LA;Narendra DP;Youle RJ
通讯作者：
Youle RJ
影响因子：
16.2
作者：
Pickrell AM;Youle RJ
通讯作者：
Youle RJ
影响因子：
13.3
作者：
Mauro-Lizcano, Marta;Esteban-Martinez, Lorena;Boya, Patricia
通讯作者：
Boya, Patricia
DOI：
10.1016/j.biocel.2014.05.010
发表时间：
2014-08
影响因子：
4
作者：
Redmann, Matthew;Dodson, Matthew;Boyer-Guittaut, Michael;Darley-Usmar, Victor;Zhang, Jianhua
通讯作者：
Zhang, Jianhua
影响因子：
6.7
作者：
Reiter, Christoph;Karagoez, Aysun Capci;Tsogoeva, Svetlana B.
通讯作者：
Tsogoeva, Svetlana B.