Sirt3-mediated mitophagy protects tumor cells against apoptosis under hypoxia.
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.
Center for Bioresources and Drug Discovery and School of Bioscience and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Aimin
A
Qiao
Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China.|Department of Pathology, Basic Medical School, Central South University, Changsha 410008, China.
Kuansong
K
Wang
Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Yunsheng
Y
Yuan
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410008, China.
Yidi
Y
Guan
Department of Pharmacology, The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
Xingcong
X
Ren
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410008, China.
Lanya
L
Li
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410008, China.
Xisha
X
Chen
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410008, China.
Feng
F
Li
Center for Vascular and Translational Medicine, The College of Pharmacy, Central South University, Changsha 410013, China.|The Third Xiangya Hospital, Central South University, Changsha 410013, China.
Alex F
AF
Chen
Department of Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha 410008, China.
Jianda
J
Zhou
Department of Pharmacology, The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
Jin-Ming
JM
Yang
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410008, China.
Yan
Y
Cheng
D000107:Acetylation; D017209:Apoptosis / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000502:physiology; D063306:Mitophagy / Q000502:physiology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000077022:Survivin; C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C466093:SIRT3 protein, human; D056566:Sirtuin 3
Sirt3; apoptosis; cancer cells; hypoxia; mitophagy