Mitochondrial electron transport chain complex III sustains hepatitis E virus replication and represents an antiviral target
Autor: | Marieke van der Heijde-Mulder, Changbo Qu, Qiuwei Pan, Mohamad S. Hakim, Ehsan Shokrollahi, Nicolaas J. H. Raat, Meng Li, Maikel P. Peppelenbosch, Yijin Wang, Shaoshi Zhang, Wenshi Wang |
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Přispěvatelé: | Gastroenterology & Hepatology, Anesthesiology |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
viruses Mitochondrion medicine.disease_cause Virus Replication Biochemistry Antiviral Agents 03 medical and health sciences chemistry.chemical_compound Electron Transport Complex III 0302 clinical medicine SDG 3 - Good Health and Well-being Hepatitis E virus Cell Line Tumor Genetics medicine Humans Molecular Biology chemistry.chemical_classification Reactive oxygen species Ribavirin MPTP Research virus diseases Electron transport chain Virology digestive system diseases Mitochondria 030104 developmental biology chemistry Mitochondrial permeability transition pore Coenzyme Q – cytochrome c reductase 030217 neurology & neurosurgery Biotechnology |
Zdroj: | FASEB Journal, 33(1), 1008-1019. FASEB |
ISSN: | 1530-6860 0892-6638 |
Popis: | Hepatitis E virus (HEV) infection has emerged as a global health problem. However, no approved medication is available, and the infection biology remains largely elusive. Electron transport chain (ETC), a key component of the mitochondria, is the main site that produces ATP and reactive oxygen species (ROS). By profiling the role of the different complexes of the mitochondrial ETC, we found that pharmacological inhibition of complex III, a well-defined drug target for the treatment of malaria and Pneumocystis pneumonia, potently restricts HEV replication. This effect demonstrated in our HEV models is equivalent to the anti-HEV potency of ribavirin, a widely used off-label treatment for patients with chronic HEV. Mechanistically, we found that this effect is independent of ATP production, ROS level, and pyridine depletion. By using pharmacological inhibitors and genetic approaches, we found that mitochondrial permeability transition pore (MPTP), a newly identified component of ETC, provides basal defense against HEV infection. HEV interferes with the opening of the MPTP. Furthermore, inhibition of the MPTP attenuated the anti-HEV effect of complex III inhibitors, suggesting that the MPTP mediates the antiviral effects of these inhibitors. These findings reveal new insights on HEV-host interactions and provide viable anti-HEV targets for therapeutic development.-Qu, C., Zhang, S., Wang, W., Li, M., Wang, Y., van der Heijde-Mulder, M., Shokrollahi, E., Hakim, M. S., Raat, N. J. H., Peppelenbosch, M. P., Pan, Q. Mitochondrial electron transport chain complex III sustains hepatitis E virus replication and represents an antiviral target. |
Databáze: | OpenAIRE |
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