tetano
Editor, Senior Moderator
Transl Neurodegener
. 2024 Dec 27;13(1):68.
doi: 10.1186/s40035-024-00458-1. SARS-CoV-2 membrane protein induces neurodegeneration via affecting Golgi-mitochondria interaction
Fang Wang[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Hailong Han[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Caifang Wang[SUP] 2 3 [/SUP], Jingfei Wang[SUP] 4 [/SUP], Yanni Peng[SUP] 2 3 [/SUP], Ye Chen[SUP] 2 3 [/SUP], Yaohui He[SUP] 5 [/SUP], Zhouyang Deng[SUP] 3 [/SUP], Fang Li[SUP] 3 [/SUP], Yikang Rong[SUP] 1 [/SUP], Danling Wang[SUP] 1 [/SUP], Wen Liu[SUP] 5 [/SUP], Hualan Chen[SUP] 4 [/SUP], Zhuohua Zhang[SUP] 6 7 8 [/SUP]
Affiliations
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 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.
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.
Keywords: Alzheimer’s disease; Brain; COVID-19; Mitochondria; PI4KIIIβ.
. 2024 Dec 27;13(1):68.
doi: 10.1186/s40035-024-00458-1. SARS-CoV-2 membrane protein induces neurodegeneration via affecting Golgi-mitochondria interaction
Fang Wang[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Hailong Han[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Caifang Wang[SUP] 2 3 [/SUP], Jingfei Wang[SUP] 4 [/SUP], Yanni Peng[SUP] 2 3 [/SUP], Ye Chen[SUP] 2 3 [/SUP], Yaohui He[SUP] 5 [/SUP], Zhouyang Deng[SUP] 3 [/SUP], Fang Li[SUP] 3 [/SUP], Yikang Rong[SUP] 1 [/SUP], Danling Wang[SUP] 1 [/SUP], Wen Liu[SUP] 5 [/SUP], Hualan Chen[SUP] 4 [/SUP], Zhuohua Zhang[SUP] 6 7 8 [/SUP]
Affiliations
- PMID: 39726060
- DOI: 10.1186/s40035-024-00458-1
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 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.
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.
Keywords: Alzheimer’s disease; Brain; COVID-19; Mitochondria; PI4KIIIβ.