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Mitochondrial OXPHOS restricts SARS-CoV-2 replication

ABSTRACT: SARS-CoV-2 rewires host metabolism to optimize virus production. While glycolysis is necessary for virus production, the importance of mitochondrial oxidative phosphorylation (OXPHOS) is unknown. The mitochondrial DNA (mtDNA) codes for 13 critical OXPHOS polypeptides plus the 22 tRNAs and 2 rRNAs for mitochondrial protein synthesis. We discovered an approximately 5 to 100-fold greater SARS-CoV-2 virus production in infected human ACE2-expressing A549 lung cells when OXPHOS was inhibited by mtDNA depletion (ρ⁰ cells), inhibition of mitochondrial translation with chloramphenicol (CAP), or chemical inhibition of OXPHOS complexes. OXPHOS inhibition led to a marked increase in the size and distribution of viral replication centers and accelerated the production and release of infectious particles, occurring approximately two hours earlier than in parental A549-ACE2 (WT) cells. Subsequently, we found that increased glycolytic capacity was required for enhanced viral replication while differences in innate immune pathway activation were not. Reintroduction of mtDNA from a well-defined maternal lineage into the ρ⁰ cells reinstated OXPHOS, impaired SARS-CoV-2 replication, and reversed associated viral and glycolytic correlates. Thus, metabolic balance regulates SARS-CoV-2 replication, with OXPHOS exerting an antiviral effect.

ORGANISM(S): Homo sapiens

PROVIDER: GSE325454 | GEO | 2026/04/30

REPOSITORIES: GEO

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Project description:Sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) restricts a broad spectrum of viruses through multifaceted mechanisms. It also limits spontaneous- and virus-induced innate immune responses by suppressing proinflammatory cytokine and type-I interferon (IFN-I) production. Some viruses escape SAMHD1 restriction and utilize SAMHD1-mediated innate immune suppression to establish effective infection through IFN antagonism. Our previous studies showed that SAMHD1 is a proviral factor facilitating replication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in human macrophages, monocytic THP-1 and epithelial-like HEK293T cell lines by suppressing IFN responses. However, it is unclear about the function of SAMHD1 in lung epithelial cells during SARS-CoV-2 infection. Here, we report that SAMHD1 knockout (KO) restricts SARS-CoV-2 replication in lung epithelial Calu-3 cells by suppressing endogenous expression of the viral receptor angiotensin-converting enzyme 2 (ACE2) via hepatocyte nuclear factor 1-alpha (HNF1α) and HNF1β. Using pseudotyped SARS-CoV-2 and lentiviral vectors, we found that SARS-CoV-2 spike protein-mediated viral entry was suppressed in SAMHD1 KO Calu-3 cells. SAMHD1 KO repressed ACE2 expression in Calu-3 cells at mRNA and protein levels. Functional analyses revealed that HNF1α and HNF1β were crucial for the endogenous ACE2 expression in Calu-3 cells. Additionally, SAMHD1 KO led to a reduction in the expression levels and ACE2-promoting function of HNF1α and HNF1β. Inhibition of IFN antiviral response by baricitinib, a Janus kinase 1 and 2 (JAK 1/2) inhibitor, did not revert the suppression of SARS-CoV-2 in SAMHD1 KO Calu-3 cells. SAMHD1 knock-in and deoxynucleoside supplementation experiments indicated that SAMHD1 expression and dNTP pool balance collectively regulated HNF1-mediated ACE2 expression in Calu-3 cells. Our findings demonstrate that SAMHD1 depletion hinders HNF1-mediated ACE2 expression and SARS-CoV-2 replication in Calu-3 cells via a novel mechanism beyond its IFN-suppressive function.

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Mitochondrial OXPHOS restricts SARS-CoV-2 replication

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