Qu 2018 FASEB J

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Qu C, Zhang S, Wang W, Li M, Wang Y, van der Heijde-Mulder M, Shokrollahi E, Hakim MS, Raat NJH, Peppelenbosch MP, Pan Q (2018) Mitochondrial electron transport chain complex III sustains hepatitis E virus replication and represents an antiviral target. FASEB J 33:1008-19.

» PMID: 30070932

Qu C, Zhang S, Wang W*, Li M, Wang Y, van der Heijde-Mulder M, Shokrollahi E, Hakim MS, Raat NJH, Peppelenbosch MP, Pan Q (2018) FASEB J

Abstract: 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.

Keywords: ETC, HEV, MPTP, Virus-host interaction Bioblast editor: Plangger M, Kandolf G


Labels: MiParea: Respiration, mt-Medicine  Pathology: Infectious 

Organism: Human  Tissue;cell: Liver  Preparation: Intact cells  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase 

Coupling state: LEAK, ROUTINE  Pathway: CIV, ROX  HRR: Oxygraph-2k 

Labels, 2018-08