SARS-CoV-2 membrane protein induces neurodegeneration via affecting Golgi-mitochondria interaction  

作　　者：Fang Wang Hailong Han Caifang Wang Jingfei Wang Yanni Peng Ye Chen Yaohui He Zhouyang Deng Fang Li Yikang Rong Danling Wang Wen Liu Hualan Chen Zhuohua Zhang 

机构地区：[1]Department of Neurosciences,Hengyang Medical School,University of South China,Hengyang 421009,China [2]Institute of Molecular Precision Medicine and Hunan Provincial Key Laboratory of Molecular Precision Medicine,Xiangya Hospital,Central South University,Changsha 410078,China [3]Hunan Provincial Key Laboratory of Medical Genetics,College of Biological Sciences,Central South University,Changsha 410078,China [4]State Key Laboratory of Veterinary Biotechnology,Harbin Veterinary Research Institute,Chinese Academy of Agricultural Sciences,Harbin 150001,China [5]Fujian Provincial Key Laboratory of Innovative Drug Target Research,School of Pharmaceutical Sciences,Xiamen University,Xiamen 361000,China

出　　处：《Translational Neurodegeneration》2024年第1期1-25,共25页转化神经变性病(英文)

基　　金：supported by grants from the National Natural Science Foundation of China(81429002,31330031,31872778,82201412);the Discipline Innovative Engineering Plan(111 Program)of China(B13036);a Key Laboratory Grant from Hunan Provincial Science and Technology Department(2016TP1006);a Science and Technology Major Project of Hunan Provincial Science and Technology Department(2018SK1030);Science and Technology Innovation Program of Hunan Province(2021SK1014);the China Postdoctoral Science Foundation(271004).

摘　　要：Background Neurological complications are a significant concern of Coronavirus Disease 2019(COVID-19).However,the pathogenic mechanism of neurological symptoms associated with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection is poorly understood.Methods We used Drosophila as a model to systematically analyze SARS-CoV-2 genes encoding structural and accessory proteins and identified the membrane protein(M)that disrupted mitochondrial functions in vivo.The M protein was stereotaxically injected to further assess its effects in the brains of wild-type(WT)and 5×FAD mice.Omics technologies,including RNA sequencing and interactome analysis,were performed to explore the mechanisms of the effects of M protein both in vitro and in vivo.Results Systematic analysis of SARS-CoV-2 structural and accessory proteins in Drosophila identified that the M protein induces mitochondrial fragmentation and dysfunction,leading to reduced ATP production,ROS overproduction,and eventually cell death in the indirect flight muscles.In WT mice,M caused hippocampal atrophy,neural apoptosis,glial activation,and mitochondrial damage.These changes were further aggravated in 5×FAD mice.M was localized to the Golgi apparatus and genetically interacted with four wheel drive(FWD,a Drosophila homolog of mammalian PI4KIIIβ)to regulate Golgi functions in flies.Fwd RNAi,but not PI4KIIIαRNAi,reversed the M-induced Golgi abnormality,mitochondrial fragmentation,and ATP reduction.Inhibition of PI4KIIIβactivity suppressed the M-induced neuronal cell death.Therefore,M induced mitochondrial fragmentation and apoptosis likely through disruption of Golgi-derived PI(4)P-containing vesicles.Conclusions M disturbs the distribution and function of Golgi,leading to mitochondrial abnormality and eventually neurodegeneration via a PI4KIIIβ-mediated mechanism.This study reveals a potential mechanism for COVID-19 neurological symptoms and opens a new avenue for development of therapeutic strategies targeting SARS-CoV-2 M or mitochondria.

关 键 词：COVID-19 Alzheimer’s disease MITOCHONDRIA PI4KⅢβ Brain 

分 类 号：R373[医药卫生—病原生物学]