Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation, 2022, Chandel et al.

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Mitochondrial respiratory chain sustains inflammation

https://medicalxpress.com/news/2022-05-mitochondrial-respiratory-chain-sustains-inflammation.html

Northwestern Medicine investigators recently discovered that the mitochondrial respiratory chain—a series of protein complexes essential for a cellular respiration and energy production—is necessary for the activation of another protein complex linked to inflammation and the progression of chronic diseases, according to a study published in Nature Immunology.


Link to journal article in the news story.

 

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Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation
https://www.nature.com/articles/s41590-022-01185-3

Abstract

The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the NLRP3 inflammasome through several mechanisms including generation of mitochondrial reactive oxygen species (ROS).

Here, we report that mitochondrial electron transport chain (ETC) complex I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement the functional loss of mitochondrial complex I or III, respectively, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function.

Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation.

Thus, the mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP, but via a ROS-independent mechanism.

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