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한국화학연구원, 현 충남대학교

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Signal Transduct. Target. Ther., May 11 2024, 9 (1) | https://doi.org/10.1038/s41392-024-01836-x SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation

Hye Jin Shin^1,6, Wooseong Lee¹, Keun Bon Ku¹, Gun Young Yoon¹, Hyun-Woo Moon¹, Chonsaeng Kim¹, Mi-Hwa Kim^1,2, Yoon-Sun Yi³, Sangmi Jun³, Bum-Tae Kim¹, Jong-Won Oh⁴, Aleem Siddiqui⁵and Seong-Jun Kim¹

¹Department of Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea;

²Gyeongnam Biohealth Research Center, Gyeongnam Branch Institute, Korea Institute of Toxicology, Jinju 52834, Republic of Korea;

³Center for Research Equipment, Korea Basic Science Institute, Cheongju, Chungcheongbuk-do 28119, Republic of Korea;

⁴Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea,

⁵Division of Infectious Diseases, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA and

⁶Present address: Department of Microbiology, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea

Correspondence: Seong-Jun Kim

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.

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형식Research article
게재일2024년 05월 (BRIC 등록일 2024-05-14)
연구진국내(교신)+국외 연구진
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