New mitochondrial DNA synthesis enables NLRP3 inflammasome activation

Abstract

Dysregulated NLRP3 inflammasome activity results in uncontrolled inflammation, which underlies many chronic diseases. Although mitochondrial damage is needed for the assembly and activation of the NLRP3 inflammasome, it is unclear how macrophages are able to respond to structurally diverse inflammasome-activating stimuli. Here we show that the synthesis of mitochondrial DNA (mtDNA), induced after the engagement of Toll-like receptors, is crucial for NLRP3 signalling. Toll-like receptors signal via the MyD88 and TRIF adaptors to trigger IRF1-dependent transcription of CMPK2, a rate-limiting enzyme that supplies deoxyribonucleotides for mtDNA synthesis. CMPK2-dependent mtDNA synthesis is necessary for the production of oxidized mtDNA fragments after exposure to NLRP3 activators. Cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation. The dependence on CMPK2 catalytic activity provides opportunities for more effective control of NLRP3 inflammasome-associated diseases.

The rOX‐stars of inflammation: links between the inflammasome and mitochondrial meltdown

“…75 In another, TLR4 ligation by LPS (signal 1) upregulated mtDNA synthesis, while NLRP3 activators (signal 2; ATP, nigericin) promoted colocalisation of oxidised mtDNA with the NLRP3 inflammasome. 76 In all, these reports suggest a model in which mtDNA liberation from mitochondria occurs prior to, and is required for, activation of the NLRP3 inflammasome (Figure 2a). NLRP3 can also sense cytosolic DNA indirectly, via cell signalling through the cyclic GMP-AMP synthase (cGAS)/stimulator of IFN genes (STING) axis.…”

Mitochondria in the biology, pathogenesis, and treatment of hepatitis virus infections

“…Even though hepatocytes contain hundreds of copies of mtDNA, it is possible that the combination of mtDNA deletions and point mutations, together with mtDNA strand breaks by increased reactive oxygen species (ROS), could reach a threshold sufficient to induce mitochondrial dysfunction, contributing to the pathogenesis of viral hepatitis. Very recently, it has been reported that new mtDNA synthesis can activate the NLRP3 inflammasome . As described, activation of NLRP3 inflammasome is closely related to the pathogenesis of chronic liver diseases, including viral hepatitis …”

Debating Eukaryogenesis—Part 1: Does Eukaryogenesis Presuppose Symbiosis Before Uptake?

“…The authors of the study hypothesize that the new DNA, not packaged in condensed nucleoid structures yet, would be more susceptible to oxidation and subsequent fragmentation by nuclease(s). [ 77 ] These fragments are then released via membrane pores, opened by NLRP3 activators. This convergence of many signals on oxidative damage in mitochondria seems indicative of an old, evolutionarily basic, eukaryotic pathway.…”