Sirt3-mediated mitophagy protects tumor cells against apoptosis under hypoxia

// Aimin Qiao 1, * , Kuansong Wang 4, 5, * , Yunsheng Yuan 7, * , Yidi Guan 2 , Xingcong Ren 3 , Lanya Li 2 , Xisha Chen 2 , Feng Li 2 , Alex F. Chen 8, 9 , Jianda Zhou 6 , Jin-Ming Yang 3 , Yan Cheng 2 1 Center for Bioresources and Drug Discovery and School of Bioscience and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China 2 Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410008, China 3 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 4 Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China 5 Department of Pathology, Basic Medical School, Central South University, Changsha 410008, China 6 Department of Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha 410008, China 7 Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China 8 Center for Vascular and Translational Medicine, The College of Pharmacy, Central South University, Changsha 410013, China 9 The Third Xiangya Hospital, Central South University, Changsha 410013, China * These authors contributed equally to this work Correspondence to: Yan Cheng, email: yancheng@csu.edu.cn Jin-Ming Yang, email: jyang2@hmc.psu.edu Jianda Zhou, email: csuzhoujianda@163.com Keywords: Sirt3, mitophagy, hypoxia, apoptosis, cancer cells Received: March 04, 2016      Accepted: May 05, 2016      Published: May 30, 2016 ABSTRACT 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.