Ginsenoside Rg3 restores hepatitis C virus-induced aberrant mitochondrial dynamics and inhibits virus propagation.
Hepatitis C virus (HCV) alters mitochondrial dynamics associated with persistent viral infection and suppression of innate immunity. Mitochondrial dysfunction is also a pathologic feature of direct-acting antiviral (DAA) treatment. Despite the high efficacy of DAAs, their use in treating patients with chronic hepatitis C in interferon-sparing regimens occasionally produces undesirable side effects such as fatigue, migraine, and other conditions, which may be linked to mitochondrial dysfunction. Here, we show that clinically prescribed DAAs, including sofosbuvir, affect mitochondrial dynamics. To counter these adverse effects, we examined HCV-induced and DAA-induced aberrant mitochondrial dynamics modulated by ginsenoside, which is known to support healthy mitochondrial physiology and the innate immune system. We screened several ginsenoside compounds showing antiviral activity using a robust HCV cell culture system. We investigated the role of ginsenosides in antiviral efficacy, alteration of mitochondrial transmembrane potential, abnormal mitochondrial fission, its upstream signaling, and mitophagic process caused by HCV infection or DAA treatment. Only one of the compounds, ginsenoside Rg3 (G-Rg3), exhibited notable and promising anti-HCV potential. Treatment of HCV-infected cells with G-Rg3 increased HCV core protein-mediated reduction in the expression level of cytosolic p21, required for increasing cyclin-dependent kinase 1 activity, which catalyzes Ser616 phosphorylation of dynamin-related protein 1. The HCV-induced mitophagy, which follows mitochondrial fission, was also rescued by G-Rg3 treatment.



G-Rg3 inhibits HCV propagation. Its antiviral mechanism involves restoring the HCV-induced dynamin-related protein 1-mediated aberrant mitochondrial fission process, thereby resulting in suppression of persistent HCV infection. (Hepatology 2017;66:758-771).
Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, South Korea.
Seong-Jun
SJ
Kim
Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, South Korea.
Jae Young
JY
Jang
Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, South Korea.
Eun-Jung
EJ
Kim
Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, South Korea.
Eun Kyung
EK
Cho
Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, South Korea.
Dae-Gyun
DG
Ahn
Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, South Korea.
Chonsaeng
C
Kim
Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, South Korea.
Han Seul
HS
Park
Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, South Korea.
Soung Won
SW
Jeong
Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, South Korea.
Sae Hwan
SH
Lee
Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, South Korea.
Sang Gyune
SG
Kim
Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, South Korea.
Young Seok
YS
Kim
Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, South Korea.
Hong Soo
HS
Kim
Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, South Korea.
Boo Sung
BS
Kim
Department of Medicine, University of California, San Diego, La Jolla, CA.
Jihyung
J
Lee
Department of Medicine, University of California, San Diego, La Jolla, CA.|Division of Infectious Diseases, University of California, San Diego, La Jolla, CA.
Aleem
A
Siddiqui
D001707:Biopsy, Needle; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D036145:Ginsenosides / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007150:Immunohistochemistry; D008930:Mitochondria, Liver / Q000187:drug effects*; D063154:Mitochondrial Dynamics / Q000187:drug effects* / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012494:Sampling Studies; D014779:Virus Replication / Q000187:drug effects*
D036145:Ginsenosides; C097367:ginsenoside Rg3