ArticleHuman molecular genetics2023
Activation of the cGAS-STING innate immune response in cells with deficient mitochondrial topoisomerase TOP1MT.
Article in Human molecular genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 31 citations in OpenAlex.
- From mitochondria to innate immunity: The mtDNA-driven cGAS/STING-NLRP3 cascade and its therapeutic implications in neurodegenerative diseases (Review).Experimental and therapeutic medicine · 2026Review
- Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis.Brain : a journal of neurology · 2026Review
- Article
- Luteolin ameliorates diabetic retinopathy through activation of the Nrf2/Keap1 and SIRT3/AMPK antioxidant axes and suppression of cGAS-STING and Wnt/β-catenin pathways in experimental rats.Journal of physiology and biochemistry · 2026Article
- Disruption of sphingolipid metabolism triggers lung vascular inflammation and aging-like changes under hypoxia through VDAC1-mediated mitochondrial DNA release.Apoptosis : an international journal on programmed cell death · 2026Article
- Remodeling of Metabolic and Secretory Organelles During Oncogenic and Oncomodulatory Viral Infections.Viruses · 2026Review
- Mitochondrial DNA-Mediated Immune Activation After Resuscitation From Cardiac Arrest.Journal of the American Heart Association · 2026Article
- Mitochondrial DNA in systemic lupus erythematosus: pathogenic mechanisms, clinical biomarkers, and precision therapeutic strategies.Frontiers in immunology · 2026Review
- Article
- The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation.Life science alliance · 2025Article
- Mitochondria - the CEO of the cell.Journal of cell science · 2025Review
- Mitochondrial DNA signals driving immune responses: Why, How, Where?Cell communication and signaling : CCS · 2025Review
- Mitochondrial DNA in Exercise-Mediated Innate Immune Responses.International journal of molecular sciences · 2025Review
- Mitochondrial DNA depletion syndrome and its cardiac complication.Frontiers in cardiovascular medicine · 2025Review
- Cell-free mitochondrial DNA as a pro-inflammatory agent in blood circulation: mechanisms, therapeutic implications, and clinical challenges in immune dysregulation.Frontiers in immunology · 2025Review
- Gene Expression Dysregulation in Whole Blood of Patients withInternational journal of molecular sciences · 2024Article
- Mitochondrial topoisomerase I (Top1MT) prevents the onset of metabolic dysfunction-associated steatohepatitis (MASH) in mice.bioRxiv : the preprint server for biology · 2024Article
- DNA topology: A central dynamic coordinator in chromatin regulation.Current opinion in structural biology · 2024Review
- Mitochondrial DNA release and sensing in innate immune responses.Human molecular genetics · 2024Review
- Mitochondrial DNA Release in Innate Immune Signaling.Annual review of biochemistry · 2023Review
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Authors and funding
16 authors at 9 institutions in 3 countries.
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Abstract
The recognition that cytosolic mitochondrial DNA (mtDNA) activates cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) innate immune signaling has unlocked novel disease mechanisms. Here, an uncharacterized variant predicted to affect TOP1MT function, P193L, was discovered in a family with multiple early onset autoimmune diseases, including Systemic Lupus Erythematosus (SLE). Although there was no previous genetic association between TOP1MT and autoimmune disease, the role of TOP1MT as a regulator of mtDNA led us to investigate whether TOP1MT could mediate the release of mtDNA to the cytosol, where it could then activate the cGAS-STING innate immune pathway known to be activated in SLE and other autoimmune diseases. Through analysis of cells with reduced TOP1MT expression, we show that loss of TOP1MT results in release of mtDNA to the cytosol, which activates the cGAS-STING pathway. We also characterized the P193L variant for its ability to rescue several TOP1MT functions when expressed in TOP1MT knockout cells. We show that the P193L variant is not fully functional, as its re-expression at high levels was unable to rescue mitochondrial respiration deficits, and only showed partial rescue for other functions, including repletion of mtDNA replication following depletion, nucleoid size, steady state mtDNA transcripts levels and mitochondrial morphology. Additionally, expression of P193L at endogenous levels was unable to rescue mtDNA release-mediated cGAS-STING signaling. Overall, we report a link between TOP1MT and mtDNA release leading to cGAS-STING activation. Moreover, we show that the P193L variant has partial loss of function that may contribute to autoimmune disease susceptibility via cGAS-STING mediated activation of the innate immune system.
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