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

作　　者：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 

机构地区：[1]Department of Convergent Research of Emerging Virus Infection,Korea Research Institute of Chemical Technology,Daejeon 34114,Republic of Korea [2]Gyeongnam Biohealth Research Center,Gyeongnam Branch Institute,Korea Institute of Toxicology,Jinju 52834,Republic of Korea [3]Center for Research Equipment,Korea Basic Science Institute,Cheongju,Chungcheongbuk-do 28119,Republic of Korea [4]Department of Biotechnology,Yonsei University,Seoul 03722,Republic of Korea [5]Division of Infectious Diseases,School of Medicine,University of California,San Diego,La Jolla,CA 92093,USA [6]Present address:Department of Microbiology,Chungnam National University School of Medicine,Daejeon 35015,Republic of Korea

出　　处：《Signal Transduction and Targeted Therapy》2024年第6期2702-2715,共14页信号转导与靶向治疗（英文）

基　　金：supported in part by the National Research Council of Science&Technology grant by the Korea government(CRC-16-01-KRICT);the Korea Research Institute of Chemical Technology(KRICT)(KK2333-20);the National Research Foundation of Korea(NRF-2021M3E5E3080540,RS-2023-00248135);the BK 21 FOUR Program by the Chungnam National University Research Grant,2023.

摘　　要：Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is a‘highly transmissible respiratory pathogen,leading to severe multiorgan damage.However,knowledge regarding SARS-CoV-2-induced cellular alterations is limited.In this study,we report that SARSCoV-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 RNAnucleocapsid 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.

关 键 词：alterations ABERRANT thereby 

分 类 号：R373[医药卫生—病原生物学]