Mitochondrial morphodynamics alteration induced by influenza virus infection as a new antiviral strategy, Irene Pila-Castellanos et al, 2021

Andy · Feb 18, 2021

Influenza virus infections are major public health threats due to their high rates of morbidity and mortality. Upon influenza virus entry, host cells experience modifications of endomembranes, including those used for virus trafficking and replication. Here we report that influenza virus infection modifies mitochondrial morphodynamics by promoting mitochondria elongation and altering endoplasmic reticulum-mitochondria tethering in host cells. Expression of the viral RNA recapitulates these modifications inside cells. Virus induced mitochondria hyper-elongation was promoted by fission associated protein DRP1 relocalization to the cytosol, enhancing a pro-fusion status. We show that altering mitochondrial hyper-fusion with Mito-C, a novel pro-fission compound, not only restores mitochondrial morphodynamics and endoplasmic reticulum-mitochondria contact sites but also dramatically reduces influenza replication. Finally, we demonstrate that the observed Mito-C antiviral property is directly connected with the innate immunity signaling RIG-I complex at mitochondria. Our data highlight the importance of a functional interchange between mitochondrial morphodynamics and innate immunity machineries in the context of influenza viral infection.

Author summary
Influenza virus infections cause significant diseases and socio-economic burden. The current therapeutic arsenal is restricted to drugs that essentially target two proteins of the virus. In this study, we investigated endomembrane modifications inside cells following influenza virus infection. We find remarkable elongation of mitochondria associated with a reduction in the number of contact sites between mitochondria and endoplasmic reticulum, platforms known to be critical for innate immunity regulation. We demonstrated that the sole expression of a fragment of the viral genome is sufficient to provoke these modifications and we identified how the main drivers of the mitochondria fusion/fission machinery behave to favor such an elongated state. We introduce potential application of Mito-C, a new drug that inhibits influenza virus replication by counteracting these membrane modifications. We finally demonstrated that the functional result of this action is a booster of the innate immune response of the cell. Thus, Mito-C has a broad spectrum potential to fight other RNA viruses, described or expected to induce similar membrane modifications (eg coronaviruses, flaviviruses, etc…).
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Open access, https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009340

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Mitochondrial morphodynamics alteration induced by influenza virus infection as a new antiviral strategy, Irene Pila-Castellanos et al, 2021

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Mitochondrial morphodynamics alteration induced by influenza virus infection as a new antiviral strategy, Irene Pila-Castellanos et al, 2021

Andy Committee Member

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