Mathilde Broquiere, INRS - Centre Armand-Frappier Santé Biotechnologie

Mathilde Broquiere (1), Viviana Andrea Barragan (1), Anaïs Rasquier (1), Anaïs Anton (1), Federica Camerota (2) Mirko Cortese (2) and Laurent Chatel Chaix (1) - (1) Institut National de la Recherche Scientifique, Centre Armand-Frappier Santé Biotechnologie, Laval, Canada (2)Telethon Institute of Genetics and Medicine, Pozzuoli, Italy

Suppressing & Conquering

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of COVID-19. With the challenges of achieving collective immunity and the ongoing improvement of antiviral treatments for COVID-19, it remains crucial to identify novel therapeutic targets. SARS-CoV-2 infection induces endoplasmic reticulum (ER)-derived viral replication organelles (vRO). Mitochondria accumulate near vROs and show altered morphology, suggesting a viral hijacking of their functions to promote replication. Redistribution of mitochondria hints at a remodeling of their physical contacts with other organelles, with potential consequences on their functions, putatively dependent on the infecting viral variant. In this study, we examined whether mitochondrial contacts with other organelles are altered during infection of permissive lung cells by different SARS-CoV-2 variants (Pre-VOC, Alpha, Beta, and Delta). Confocal and electron microscopy revealed an elongation of the mitochondrial network and a marked reduction in mitochondria–ER contacts. Moreover, proximity ligation assays targeting the RRBP1–SYNJ2BP tethering complex confirmed the decrease in ER–mitochondria interactions upon infection with all variants. Furthermore, knockdown those proteins reduced viral replication, suggesting that the virus hijacks this protein complex for the benefit of viral infection. Preliminary data showed that the overexpression of ORF3a and ORF6 may contribute to these phenotypes. Ongoing studies aim to determine how these proteins affect the reticulo-mitochondrial interface and their effect on its functions, such as respiration and apoptosis. Overall, this project highlights how SARS-CoV-2 variants remodel mitochondrial networks and heterotypic organelle contacts. Ongoing experiments involving live cell imaging will provide further spatiotemporal insights into the remodeling of the mitochondrial network by SARS-CoV-2.