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MRE11-independent effects of Mirin on mitochondrial DNA integrity and cellular immune responses
Koit Aasumets1, Anu Hangas1, Georgios Fragkoulis1
1Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu 80101, Finland.
Abstract:
Mirin, a chemical inhibitor of MRE11, has been recently reported to suppress immune response triggered by mitochondrial DNA (mtDNA) breakage and release during replication stalling. We show that while Mirin reduces mitochondrial replication fork breakage in mitochondrial 3´-exonuclease MGME1 deficient cells, this effect occurs independently of MRE11. We also discovered that Mirin directly inhibits cellular immune responses, as shown by its suppression of STAT1 phosphorylation in Poly (I:C)-treated cells. Furthermore, Mirin also altered mtDNA supercoiling and accumulation of hemicatenated replication termination intermediates-hallmarks of topoisomerase dysfunction-while mitigating topological changes induced by the overexpression of mitochondrial TOP3A, including TOP3A-dependent strand breakage at the noncoding region of mtDNA. Although Mirin does not seem to inhibit TOP3A activity in vitro, our findings demonstrate its MRE11-independent effects in cells and give insight into the mechanisms of the maintenance of mtDNA integrity.
Insights
Mirin, an MRE11 inhibitor, suppresses immune responses and alters mitochondrial DNA (mtDNA) integrity. Its effects on mtDNA breakage and topoisomerase function are independent of MRE11, revealing new cellular mechanisms.
Area of Science:
- Cellular Biology
- Molecular Biology
- Immunology
Background:
- Mitochondrial DNA (mtDNA) release can trigger immune responses.
- Mirin is a known inhibitor of MRE11, implicated in DNA repair.
- Replication stalling can lead to mtDNA breakage and release.
Purpose of the Study:
- To investigate the MRE11-independent effects of Mirin on mtDNA integrity and cellular immune responses.
- To elucidate the mechanisms by which Mirin affects mtDNA replication and topology.
- To understand Mirin's impact on topoisomerase function in mitochondria.
Main Methods:
- Utilized MGME1-deficient cells to assess Mirin's effect on mtDNA breakage.
- Analyzed STAT1 phosphorylation in Poly (I:C)-treated cells to evaluate immune response suppression.
- Examined mtDNA supercoiling and replication intermediates.
- Investigated Mirin's impact on TOP3A overexpression-induced topological changes and strand breakage.
Main Results:
- Mirin reduced mtDNA replication fork breakage in MGME1-deficient cells independently of MRE11.
- Mirin suppressed cellular immune responses by inhibiting STAT1 phosphorylation.
- Mirin altered mtDNA supercoiling and accumulation of hemicatenated replication termination intermediates.
- Mirin mitigated TOP3A overexpression-induced mtDNA topological changes and strand breakage, despite no in vitro TOP3A inhibition.
Conclusions:
- Mirin exhibits MRE11-independent cellular effects.
- Mirin directly inhibits cellular immune responses.
- Mirin influences mtDNA integrity and topology, potentially through mechanisms related to topoisomerase dysfunction.
- Findings provide insight into mtDNA maintenance mechanisms.
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