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

DOI record: { "DOI": "10.1186/s40035-024-00458-1", "ISSN": [ "2047-9158" ], "URL": "http://dx.doi.org/10.1186/s40035-024-00458-1", "abstract": "<jats:title>Abstract</jats:title><jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec><jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>We used <jats:italic>Drosophila</jats:italic> 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.</jats:p>\n </jats:sec><jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>Systematic analysis of SARS-CoV-2 structural and accessory proteins in <jats:italic>Drosophila</jats:italic> 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 <jats:italic>Drosophila</jats:italic> homolog of mammalian PI4KIIIβ) to regulate Golgi functions in flies. <jats:italic>Fwd</jats:italic> RNAi, but not PI4KIIIα RNAi, reversed the M-induced Golgi abnormality, mitochondrial fragmentation, and ATP reduction. Inhibition of PI4KIIIβ activity 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.</jats:p>\n </jats:sec><jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>", "alternative-id": [ "458" ], "article-number": "68", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "25 May 2024" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "12 November 2024" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "27 December 2024" }, { "group": { "label": "Declarations", "name": "EthicsHeading" }, "name": "Ethics", "order": 1 }, { "group": { "label": "Ethics approval and consent to participate", "name": "EthicsHeading" }, "name": "Ethics", "order": 2, "value": "All animal studies had complied with all relevant ethical regulations for the animal testing and research, and were approved by the Animal Care and Use Committee of Xiangya Hospital, Central South University." }, { "group": { "label": "Consent for publication", "name": "EthicsHeading" }, "name": "Ethics", "order": 3, "value": "All authors read and approved the final manuscript." }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 4, "value": "The authors declare that they have no competing interests." } ], "author": [ { "affiliation": [], "family": "Wang", "given": "Fang", "sequence": "first" }, { "affiliation": [], "family": "Han", "given": "Hailong", "sequence": "additional" }, { "affiliation": [], "family": "Wang", "given": "Caifang", "sequence": "additional" }, { "affiliation": [], "family": "Wang", "given": "Jingfei", "sequence": "additional" }, { "affiliation": [], "family": "Peng", "given": "Yanni", "sequence": "additional" }, { "affiliation": [], "family": 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