Artesunate-induced mitophagy alters cellular redox status
| Autor: | Dongsheng Huang, Guoqing Wu, Yin Kwan Wong, Liqin Lu, Xin Sun, Chao Zhou, Jigang Wang, Liu Yang, Jianing Zhong, Liming Wang, Jianbin Zhang, Tongwei Zhao, Yew Mun Lee |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
LC3 microtubule-associated proteins 1A/1B light chain 3 Clinical Biochemistry CQ chloroquine Artesunate Apoptosis Mitochondrion CPS carbamoyl-phosphate synthase Biochemistry Parkin PC pyruvate carboxylase Neoplasms Mitophagy GSH glutathione LAMP1 lysosomal-associated membrane protein 1 lcsh:QH301-705.5 lcsh:R5-920 education.field_of_study Chemistry ROS Mitochondria Cell biology PINK1 PTEN induced putative kinase 1 SQSTM1/P62 sequestosome 1 VDAC1 voltage-dependent anion-selective channel protein 1 Artemisinin Mitochondrial fission lcsh:Medicine (General) Oxidation-Reduction Research Paper Programmed cell death Antineoplastic Agents PINK1 COX Ⅳ cytochrome c oxidase IV Antimalarials 03 medical and health sciences TOMM20 translocase of outer mitochondrial membrane 20 ROS reactive oxygen species Sequestosome 1 Humans ATP adenosine triphosphate vacuolar-type H+-ATPase (V-ATPase) ACADVL very long-chain specific acyl-CoA dehydrogenase education ACC acetyl-CoA carboxylase 1 HSP60 heat shock protein 60 kDa Organic Chemistry Autophagy Drug Repositioning TIM23 translocase of the inner membrane 23 030104 developmental biology lcsh:Biology (General) HeLa Cells |
| Zdroj: | Redox Biology Redox Biology, Vol 19, Iss, Pp 263-273 (2018) |
| ISSN: | 2213-2317 |
| DOI: | 10.1016/j.redox.2018.07.025 |
| Popis: | 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. Highlights • 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|