Dengue virus and Zika virus alter endoplasmic reticulum-mitochondria contact sites to regulate respiration and apoptosis
During infection, dengue virus (DENV) and Zika virus (ZIKV), two (ortho)flaviviruses of public health concern worldwide, induce alterations of mitochondria morphology to favor viral replication, suggesting a viral co-opting of mitochondria functions. Here, we performed an extensive transmission electron microscopy-based quantitative analysis to demonstrate that both DENV and ZIKV alter endoplasmic reticulum-mitochondria contact sites (ERMC). This correlated at the molecular level with an impairment of ERMC tethering protein complexes located at the surface of both organelles. Furthermore, virus infection modulated the mitochondrial oxygen consumption rate. Consistently, metabolomic and mitoproteomic analyses revealed a decrease in the abundance of several metabolites of the Krebs cycle and changes in the stoichiometry of the electron transport chain. Most importantly, ERMC destabilization by protein knockdown increased virus replication while dampening ZIKV-induced apoptosis. Overall, our results support the notion that flaviviruses hijack ERMCs to generate a cytoplasmic environment beneficial for sustained and efficient replication.
Authors
- Anaïs Anton (ORCID: https://orcid.org/0000-0002-3455-0882)
- Laurent Chatel‐Chaix (ORCID: https://orcid.org/0000-0002-7390-8250)
- Zaynab Nouhi
- Denis Girard (ORCID: https://orcid.org/0000-0002-3342-5027)
- Nicolas Tremblay (ORCID: https://orcid.org/0000-0003-4246-7189)
- Christopher John Neufeldt (ORCID: https://orcid.org/0000-0002-4551-1811)
- Ian Gaël Rodrigue‐Gervais
- Alain Lamarre (ORCID: https://orcid.org/0000-0002-7913-871X)
- Pietro Scaturro (ORCID: https://orcid.org/0000-0001-9098-3087)
- Wesley Freppel (ORCID: https://orcid.org/0000-0003-3628-0465)
- Clément Mazeaud
- Andreas Pichlmair (ORCID: https://orcid.org/0000-0002-0166-1367)
- Jonathan E Owen (ORCID: https://orcid.org/0000-0002-8668-9202)
- Claudia Gilbert (ORCID: https://orcid.org/0000-0002-2430-8435)
- Xavier Laulhé
- Viviana Andrea Barragan Torres
- Laura Hulea (ORCID: https://orcid.org/0000-0001-7585-7760)
- Olus Uyar (ORCID: https://orcid.org/0000-0002-6399-5573)
- Alexanne Léveillé
- Cheyanne L Bemis
- Aïssatou Aïcha Sow (ORCID: https://orcid.org/0000-0002-0500-2625)
- Mathilde Broquière
Institutions
- Leibniz Institute of Virology (LIV) (DE)
- Emory University (US)
- Hôpital Maisonneuve-Rosemont (CA)
- Institut National de la Recherche Scientifique (CA)
- German Center for Infection Research (DE)
- Fonds de Recherche du Québec - Santé (CA)
- Université du Québec (CA)
- Technical University of Munich (DE)
- Université de Montréal (CA)
Publication Details
- Journal
- iScience
- Published
- 2024-12-13
- DOI
- https://doi.org/10.1016/j.isci.2024.111599
- Citations
- 17
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 9.23
Funders
- Canadian Institutes of Health Research