title: Mitofusin-2 triggers mitochondria Ca2+ influx from the endoplasmic reticulum to induce apoptosis in hepatocellular carcinoma cells.
abstract: In previous studies, we confirmed that mitofusin-2 (Mfn2) induced apoptosis in hepatocellular carcinoma (HCC) cells. However, the exact molecular mechanism remained unclear. Mfn2 expressed lower in tumour tissues, compared with adjacent non-cancer tissues. Furthermore, Mfn2 immunostaining was very weak in HCC tissue (P < 0.05) and was significantly associated with tumour size and TNM stage (P = 0.038 and 0.040, respectively), and patients with HCC with lower Mfn2 expression had a poorer prognosis. Overexpression of Mfn2 induced HepG2 cells apoptosis, reduced the mitochondrial membrane potential (ΔΨm) and endoplasmic reticulum (ER) calcium ion (Ca(2+)) concentrations, and elevated intracellular reactive oxygen species (ROS) and mitochondrial Ca(2+) concentrations. However, when HepG2 cells overexpressing Mfn2 were treated with both heparin and RU360, there was no induction of apoptosis, decline in ΔΨm or ER Ca(2+), or increase in intracellular ROS or mitochondrial Ca(2+). We also found downregulation in the expression of mitochondrial calcium uptake1 and 2 (MICU1 and MICU2) in cells transfected with Adv-Mfn2. Thus, we confirmed that Mfn2 induced apoptosis in HCC cells by triggering influx of Ca(2+) into the mitochondria from the ER.
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China.
authors.forename: Weilin
authors.initials: W
authors.lastname: Wang
authors.affiliation: Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.
authors.forename: Jingzi
authors.initials: J
authors.lastname: Yao
authors.affiliation: Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Huang
authors.affiliation: Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.
authors.forename: Lufei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wei
authors.affiliation: Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.affiliation: Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China. Electronic address: zyzss@zju.edu.cn.
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000235:genetics; D002118:Calcium / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006493:Heparin / Q000008:administration & dosage; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000473:pathology; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009367:Neoplasm Staging; D017382:Reactive Oxygen Species / Q000378:metabolism; D017975:Ruthenium Compounds / Q000008:administration & dosage
chemical_list: D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C112020:Ru 360; D017975:Ruthenium Compounds; D006493:Heparin; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; D002118:Calcium
keywords: Heparin; InsP(3)R; Mitochondrial Ca(2+) uniporter; Mitochondrial calcium uptake 2; Mitochondrial calcium uptake1; RU360