Protective role of amantadine in mitochondrial dysfunction and oxidative stress mediated by hepatitis C virus protein expression

Giovanni Quarato, Rosella Scrima, Maria Ripoli, Francesca Agriesti, Darius Moradpour, Nazzareno Capitanio, Claudia Piccoli

Research output: Contribution to journalArticlepeer-review

Abstract

Amantadine is an antiviral and antiparkinsonian drug that has been evaluated in combination therapies against hepatitis C virus (HCV) infection. Controversial results have been reported concerning its efficacy, and its mechanism of action remains unclear. Data obtained in vitro suggested a role of amantadine in inhibiting HCV p7-mediated cation conductance. In keeping with the fact that mitochondria are responsible to ionic fluxes and that HCV infection impairs mitochondrial function, we investigated a potential role of amantadine in modulating mitochondrial function. Using a well-characterized inducible cell line expressing the full-length HCV polyprotein, we found that amantadine not only prevented but also rescued HCV protein-mediated mitochondrial dysfunction. Specifically, amantadine corrected (i) overload of mitochondrial Ca 2+; (ii) inhibition of respiratory chain activity and oxidative phosphorylation; (iii) reduction of membrane potential; and (iv) overproduction of reactive oxygen species. The effects of amantadine were observed within 15 min following drug administration and confirmed in Huh-7.5 cells transfected with an infectious HCV genome. These effects were also observed in cells expressing subgenomic HCV constructs, indicating that they are not mediated or only in part mediated by p7. Single organelle analyzes carried out on isolated mouse liver mitochondria demonstrated that amantadine induces hyperpolarization of the membrane potential. Moreover, amantadine treatment increased the calcium threshold required to trigger mitochondrial permeability transition opening. In conclusion, these results support a role of amantadine in preserving cellular bioenergetics and redox homeostasis in HCV-infected cells and unveil an effect of the drug which might be exploited for a broader therapeutic utilization.

Original languageEnglish
Pages (from-to)545-556
Number of pages12
JournalBiochemical Pharmacology
Volume89
Issue number4
DOIs
Publication statusPublished - Jun 15 2014

Keywords

  • Amantadine
  • Calcium channels
  • Hepatitis C virus
  • Inducible viral protein expression
  • Mitochondria
  • Oxidative stress

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

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