Sirt3-mediated mitophagy protects tumor cells against apoptosis under hypoxia
| Autor: | Yan Cheng, Lan-ya Li, Feng Li, Aimin Qiao, Xi-Sha Chen, Yunsheng Yuan, Xingcong Ren, Jianda Zhou, Jin Ming Yang, Kuansong Wang, Yi-Di Guan, Alex F. Chen |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
SIRT3 Cell Survival Survivin Ubiquitin-Protein Ligases Mitochondrial Degradation Apoptosis Mitochondrion Parkin Inhibitor of Apoptosis Proteins 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Sirtuin 3 Mitophagy Medicine Humans RNA Small Interfering Membrane Potential Mitochondrial business.industry Voltage-Dependent Anion Channel 1 Autophagy Acetylation Flow Cytometry Cell Hypoxia Cell biology Mitochondria 030104 developmental biology Oncology Microscopy Fluorescence 030220 oncology & carcinogenesis Cancer cell Myeloid Cell Leukemia Sequence 1 Protein RNA Interference business Reactive Oxygen Species VDAC1 Signal Transduction |
| Zdroj: | Oncotarget. 7(28) |
| ISSN: | 1949-2553 |
| Popis: | Sirt3, a mitochondrial deacetylase, participates in the regulation of multiple cellular processes through its effect on protein acetylation. The objective of this study was to explore the role of Sirt3 in the mitochondrial autophagy (mitophagy), a process of the specific autophagic elimination of damaged mitochondria. We found that silencing of Sirt3 expression in human glioma cells by RNA interference blunted the hypoxia-induced the localization of LC3 on the mitochondria, and the degradation of mitochondria. These results suggest an important involvement of this protein deacetylase in the induction of mitophagy in cancer cells subjected to hypoxia. Further, we demonstrated that Sirt3 activated the hypoxia-induced mitophagy by increasing the interaction of VDAC1 with Parkin. In the cells subjected to hypoxia, inhibition of Sirt3-mediated mitophagy further decreased the mitochondrial membrane potential, and increased the accumulation of ROS that triggers the degradation of anti-apoptotic proteins Mcl-1 and survivin through the proteasomal pathway. Silencing of Sirt3 expression also promoted apoptosis, and enhanced the sensitivity of cancer cells to hypoxia. The regulatory role of Sirt3 in autophagy and apoptosis was also observed in human breast cancer cells. The results of the current study reveal Sirt3 as a novel regulator coupling mitophagy and apoptosis, two important cellular processes that determine cellular survival and death. |
| Databáze: | OpenAIRE |
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