ArticleFrontiers in immunology2023
SARS-COV-2 viroporins activate the NLRP3-inflammasome by the mitochondrial permeability transition pore.
Article in Frontiers in immunology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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42 citing papers in PubMed, 53 citations in OpenAlex.
- Review
- Involvement of NLRP3 Inflammasome in Methamphetamine Augmentation of SARS-CoV-2 N-Protein-Induced Neuroinflammation in Rat Microglial Cells.International journal of molecular sciences · 2026Article
- ZDHHC18-Mediated Palmitoylation of ORF3a Promotes SARS-CoV-2 Pathogenesis by Antagonizing TRIM16-Mediated Ubiquitination and Proteasomal Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Mitochondrial OXPHOS restricts SARS-CoV-2 replication.Science advances · 2026Article
- STING is a key driver of Japanese encephalitis virus induced inflammatory response.Communications biology · 2026Article
- Infectious bronchitis virus accessory protein 3a induces renal inflammatory injury by activating the NLRP3 inflammasome via ER calcium mobilization and mitochondrial ROS production.Journal of virology · 2026Article
- SARS-CoV-2 envelope protein mitochondrial localization reveals host metabolic disruption.The Journal of biological chemistry · 2026Article
- The Open Reading Frame 7b of the SARS-CoV-2 Disperse Trans-Golgi and Activate the NLRP3 Inflammasome.Journal of medical virology · 2026Article
- Defective RNA Polymerase III sensing of mitochondrial DNA in pulmonary epithelial cells impairs type I IFN immunity to SARS-CoV-2.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Decoding the gut microbiota-mitochondrial-inflammasome axis in cardiovascular disease.Molecular and cellular biochemistry · 2026Review
- Host mitochondrial DNA in bacterial pathogenesis: Friend, Foe, or Both?Archives of microbiology · 2026Review
- Mechanistic insights and challenges in mitochondrial regulation of macrophage polarization and inflammatory responses.Frontiers in physiology · 2026Review
- Structural and Computational Insights into the Attenuated Innate Immune Recognition of the SARS-CoV-2 N15 Lineage, an Early-Pandemic Variant.Computational and structural biotechnology journal · 2026Article
- Multi-omics analysis of long COVID (post-COVID-19 condition) reveals persistent mitochondrial dysfunction, suppressed oxidative phosphorylation, and immune dysregulation.Frontiers in immunology · 2026Article
- Avian coronavirus IBV-induced activation of the NLRP3-Caspase-1-IL-1β axis in renal collecting ducts contributes to nephropathogenesis.Journal of virology · 2025Article
- Mechanisms of Mitochondrial Impairment by SARS-CoV-2 Proteins: A Nexus of Pathogenesis with Significant Biochemical and Clinical Implications.International journal of molecular sciences · 2025Review
- Viroporins: emerging viral infection mechanisms and therapeutic targets.Journal of virology · 2025Review
- SARS-CoV-2 encoded ORF3a interacts with YY1 to promote latent HCMV reactivation.PLoS pathogens · 2025Article
- SARS-CoV-2 ORF3a drives dynamic dense body formation for optimal viral infectivity.Nature communications · 2025Article
- Mitochondrial DNA signals driving immune responses: Why, How, Where?Cell communication and signaling : CCS · 2025Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
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Abstract
Background: Compared to healthy controls, severe COVID19 patients display increased levels of activated NLRP3-inflammasome (NLRP3-I) and interleukin (IL)-1β. SARS-CoV-2 encodes viroporin proteins E and Orf3a(2-E+2-3a) with homologs to SARS-CoV-1, 1-E+1-3a, which elevate NLRP3-I activation; by an unknown mechanism. Thus, we investigated how 2-E+2-3a activates the NLRP3-I to better understand the pathophysiology of severe COVID-19. Methods: We generated a polycistronic expression-vector co-expressing 2-E+2-3a from a single transcript. To elucidate how 2-E+2-3a activates the NLRP3-I, we reconstituted the NLRP3-I in 293T cells and used THP1-derived macrophages to monitor the secretion of mature IL-1β. Mitochondrial physiology was assessed using fluorescent microscopy and plate reader assays, and the release of mitochondrial DNA (mtDNA) was detected from cytosolic-enriched fractions using Real-Time PCR. Results: Expression of 2-E+2-3a in 293T cells increased cytosolic Ca++ and elevated mitochondrial Ca++, taken up through the MCUi11-sensitive mitochondrial calcium uniporter. Increased mitochondrial Ca++ stimulated NADH, mitochondrial reactive oxygen species (mROS) production and the release of mtDNA into the cytosol. Expression of 2-E+2-3a in NLRP3-I reconstituted 293T cells and THP1-derived macrophages displayed increased secretion of IL-1β. Increasing mitochondrial antioxidant defenses via treatment with MnTBAP or genetic expression of mCAT abolished 2-E+2-3a elevation of mROS, cytosolic mtDNA levels, and secretion of NLRP3-activated-IL-1β. The 2-E+2-3a-induced release of mtDNA and the secretion of NLRP3-activated-IL-1β were absent in cells lacking mtDNA and blocked in cells treated with the mitochondrial-permeability-pore(mtPTP)-specific inhibitor NIM811. Conclusion: Our findings revealed that mROS activates the release of mitochondrial DNA via the NIM811-sensitive mitochondrial-permeability-pore(mtPTP), activating the inflammasome. Hence, interventions targeting mROS and the mtPTP may mitigate the severity of COVID-19 cytokine storms.
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