首页|SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation

SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation

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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.

Hye Jin Shin、Wooseong Lee、Keun Bon Ku、Gun Young Yoon、Hyun-Woo Moon、Chonsaeng Kim、Mi-Hwa Kim、Yoon-Sun Yi、Sangmi Jun、Bum-Tae Kim、Jong-Won Oh、Aleem Siddiqui、Seong-Jun Kim

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

Department of Microbiology,Chungnam National University School of Medicine,Daejeon 35015,Republic of Korea

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

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

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

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

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National Research Council of Science &Technology grant by the Korea governmentKorea Research Institute of Chemical Technology(KRICT)National Research Foundation of KoreaNational Research Foundation of KoreaBK 21 FOUR Program by the Chungnam National University Research Grant,2023

CRC-16-01-KRICTKK2333-20NRF-2021M3E5E3080540RS-2023-00248135

2024

10.1038/s41392-024-01836-x

信号转导与靶向治疗(英文)

信号转导与靶向治疗(英文)

CSTPCD
ISSN：
年,卷(期)：2024.9(6)