MicroRNA-181a suppresses parkin-mediated mitophagy and sensitizes neuroblastoma cells to mitochondrial uncoupler-induced apoptosis

// Min Cheng 1, 2, * , Lei Liu 1, 2, * , Yuanzhi Lao 3 , Weijie Liao 1, 2 , Meijian Liao 1, 2 , Xuan Luo 2, 4 , Jiangbin Wu 2 , Weidong Xie 2 , Yaou Zhang 2, 5 , Naihan Xu 2, 5 1 School of Life Sciences, Tsinghua University, Beijing 100084, China 2 Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China 3 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China 4 Department of Chemistry, Tsinghua University, Beijing 100084, P.R. China 5 Open FIESTA Center, Tsinghua University, Shenzhen 518055, P.R. China * These authors have contributed equally to this work Correspondence to: Naihan Xu, email: xu.naihan@sz.tsinghua.edu.cn Yaou Zhang, email: zhangyo@sz.tsinghua.edu.cn Keywords: microRNA, mitochondria, mitophagy, parkin, apoptosis Received: January 11, 2016 Accepted: May 20, 2016 Published: June 02, 2016 ABSTRACT Damage to mitochondria often results in the activation of both mitophagy and mitochondrial apoptosis. The elimination of dysfunctional mitochondria is necessary for mitochondrial quality maintenance and efficient energy supply. Here we report that miR-181a is a novel inhibitor of mitophagy. miR-181a is downregulated by mitochondrial uncouplers in human neuroblastoma SH-SY5Y cells. Overexpression of miR-181a inhibits mitochondrial uncoupling agents-induced mitophagy by inhibiting the degradation of mitochondrial proteins without affecting global autophagy. Knock down of endogenous miR-181a accelerates the autophagic degradation of damaged mitochondria. miR-181a directly targets Parkin E3 ubiquitin ligase and partially blocks the colocalization of mitochondria and autophagosomes/lysosomes. Re-expression of exogenous Parkin restores the inhibitory effect of miR-181a on mitophagy. Furthermore, miR-181a increases the sensitivity of neuroblastoma cells to mitochondrial uncoupler-induced apoptosis, whereas miR-181a antagomir prevents cell death. Because mitophagy defects are associated with a variety of human disorders, these findings indicate an important link between microRNA and Parkin-mediated mitophagy and highlights a potential therapeutic strategy for human diseases.