Elsa Sanchez-Lopez et al have discovered that eliminating damaged mitochondria before they trigger excessive inflammation may help alleviate chronic inflammatory diseases. NLRP3 inflammasome- a multiprotein oligomer is responsible for the activation of inflammatory responses in the body. However, during mitochondrial damage due to stress or bacterial toxins NLRP3 can remain ‘switched on’ leading to excess inflammation. Researchers have found that NLRP3 is deactivated when damaged mitochondria are eliminated during cellular cycling called mitophagy. Scientists showed that mitophagy can be induced by inhibiting the uptake of the nutrient choline by mitochondria. Choline is taken up through specific transporters and metabolized by enzyme choline kinase (ChoK). Decreasing the uptake of choline altered the mitochondrial lipid profile, decreasing the ATP synthesis in mitochondria. This activates the energy sensor AMP-activated protein kinase (AMPK) which stimulates mitophagy. Choline uptake by cells was prevented by inhibiting choline transporter CTL1 or choline phosphorylation by using ChoK inhibitors. This attenuated the NLRP3 inflammasome activation and IL-1β and IL-18 cytokine production in stimulated macrophages. Researchers also showed that on treating a mouse model of Muckle-Wells syndrome with ChoK inhibitors reversed the inflammation. The in vivo study
in mice showed that treatment with ChoK inhibitors prevented acute inflammation caused by uric acid accumulation (seen in gout)
and a bacterial toxin. ChoK inhibitor treatment also reversed chronic inflammation associated with a genetic disease called Muckle-Well Syndrome in mice which is caused by mutations in NLRP3 genes.
Source: Cell Metabolism April 11, 2019 DOI: https://doi.org/10.1016/j.cmet.2019.03.011