1. SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation
- Author
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Shin, Hye Jin, Lee, Wooseong, Ku, Keun Bon, Yoon, Gun Young, Moon, Hyun-Woo, Kim, Chonsaeng, Kim, Mi-Hwa, Yi, Yoon-Sun, Jun, Sangmi, Kim, Bum-Tae, Oh, Jong-Won, Siddiqui, Aleem, and Kim, Seong-Jun
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Coronaviruses ,Infectious Diseases ,Coronaviruses Therapeutics and Interventions ,Lung ,Emerging Infectious Diseases ,2.1 Biological and endogenous factors ,Infection ,Good Health and Well Being ,SARS-CoV-2 ,Mitochondria ,Humans ,Animals ,Mice ,COVID-19 ,ErbB Receptors ,Virus Replication ,Energy Metabolism ,Vero Cells ,Chlorocebus aethiops ,Antiviral Agents ,COVID-19 Drug Treatment ,Membrane Potential ,Mitochondrial ,Oxidative Phosphorylation ,Signal Transduction - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 'highly transmissible respiratory pathogen, leading to severe multi-organ damage. However, knowledge regarding SARS-CoV-2-induced cellular alterations is limited. In this study, we report that SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral infection. SARS-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNA-nucleocapsid cluster, thereby abnormally promoting mitochondrial elongation and the OXPHOS process, followed by enhancing ATP production. Furthermore, SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking, contributing to abnormal OXPHOS process and viral propagation. Approved EGFR inhibitors remarkably reduce SARS-CoV-2 propagation, among which vandetanib exhibits the highest antiviral efficacy. Treatment of SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation, thereby resulting in the reduction of SARS-CoV-2 propagation. Furthermore, oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung inflammation. Vandetanib also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern, including alpha, beta, delta and omicron, in in vitro cell culture experiments. Taken together, our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation, suggesting that EGFR is an attractive host target for combating COVID-19.
- Published
- 2024