“Oxidized Mitochondrial DNA” – a missing link between apoptosis and inflammasome activation

· TGI - Health
Authors

In a recent article by Kenichi Shimada et.al., it was reported that in the presence of signal 1 (NF-κB), the NLRP3 inflammasome was activated by mitochondrial apoptotic signaling that licensed production of interleukin-1β (IL-1β). NLRP3 secondary signal activators such as ATP induced mitochondrial dysfunction and apoptosis, resulting in release of oxidized mitochondrial DNA (mtDNA) into the cytosol, where it bound to and activated the NLRP3 inflammasome.

The antiapoptotic protein Bcl-2 inversely regulated mitochondrial dysfunction and NLRP3 inflammasome activation. Mitochondrial DNA directly induced NLRP3 inflammasome activation, because macrophages lacking mtDNA had severely attenuated IL-1β production, yet still underwent apoptosis. Both binding of oxidized mtDNA to the NLRP3 inflammasome and IL-1β secretion could be competitively inhibited by the oxidized nucleoside 8-OH-dG.

Thus, the data reveal that oxidized mtDNA released during programmed cell death causes activation of the NLRP3 inflammasome. These results provide a missing link between apoptosis and inflammasome activation, via binding of cytosolic oxidized mtDNA to the NLRP3 inflammasome.

Highlights

► NLRP3 activators induce apoptosis that activates the inflammasome

► Apoptosis is required for NLRP3 activation

► Oxidized mtDNA that is generated during apoptosis binds to NLRP3 and activates it

► The oxidized nucleoside 8-OH-dG inhibits mtDNA binding to NLRP3

source

sciencedirect

Related articles

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Source: pubmed

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source: wiley

 

 

 

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