SARS-CoV-2 Nsp8 induces mitophagy by damaging mitochondria

Shan Zong; Yan Wu; Weiling Li; Qiang You; Qian Peng; Chenghai Wang; Pin Wan; Tao Bai; Yanling Ma; Binlian Sun; Jialu Qiao

doi:10.1016/j.virs.2023.05.003

SARS-CoV-2 Nsp8 induces mitophagy by damaging mitochondria

Virol Sin. 2023 Aug;38(4):520-530. doi: 10.1016/j.virs.2023.05.003. Epub 2023 May 6.

Authors

Shan Zong¹, Yan Wu², Weiling Li¹, Qiang You¹, Qian Peng¹, Chenghai Wang¹, Pin Wan¹, Tao Bai³, Yanling Ma⁴, Binlian Sun⁵, Jialu Qiao⁶

Affiliations

¹ Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, 430056, China.
² State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
³ Division of Gastroenterology, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, 430030, China.
⁴ Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, 430030, China.
⁵ Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, 430056, China. Electronic address: binlian17@jhun.edu.cn.
⁶ Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, 430056, China; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, 442000, China. Electronic address: jialuqiao@jhun.edu.cn.

Abstract

Autophagy plays an important role in the interaction between viruses and host cells. SARS-CoV-2 infection can disrupt the autophagy process in target cells. However, the precise molecular mechanism is still unknown. In this study, we discovered that the Nsp8 of SARS-CoV-2 could cause an increasing accumulation of autophagosomes by preventing the fusion of autophagosomes and lysosomes. From further investigation, we found that Nsp8 was present on mitochondria and can damage mitochondria to initiate mitophagy. The results of experiments with immunofluorescence revealed that Nsp8 induced incomplete mitophagy. Moreover, both domains of Nsp8 orchestrated their function during Nsp8-induced mitophagy, in which the N-terminal domain colocalized with mitochondria and the C-terminal domain induced auto/mitophagy. This novel finding expands our understanding of the function of Nsp8 in promoting mitochondrial damage and inducing incomplete mitophagy, which helps us to understand the etiology of COVID-19 as well as open up new pathways for creating SARS-CoV-2 treatment methods.

Keywords: Autophagy; Mitochondrial damage; Mitophagy; Nsp8; SARS-CoV-2.