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Mitochondria and the NLRP3 inflammasome: physiological and pathological relevance

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Abstract

The NLRP3 inflammasome is assembled and activated in certain types of myeloid cells upon sensing microbe-derived toxins or host-derived danger signals. Activation of the NLRP3 inflammasome by endogenous ligands has been discovered in various disorders, including metabolic syndrome, type 2 diabetes, atherosclerosis, gout, reperfusion injury of the heart, neurodegeneration, such as Alzheimer’s disease, chronic kidney diseases, and macular degeneration of the eyes. Despite the potential significance of the NLRP3 inflammasome in the pathogenesis of several diseases, details on the activation mechanism of the NLRP3 inflammasome by a variety of stimulators have yet to be reported. Emerging evidence suggests that mitochondrial events are associated with NLRP3 activation in disease conditions. Mitochondrial dysfunction acts upstream of NLRP3 activation by providing reactive oxygen species (ROS) to trigger NLRP3 oligomerization or by inducing α-tubulin acetylation to relocate mitochondria to the proximity of NLRP3. In addition, mitochondria work as a platform for inflammasome assembly. Mitochondrial events may also lie downstream of NLRP3 activation. While the molecular mechanisms of mitochondrial dysfunction associated with NLRP3 activation are still unclear, they may involve the perturbation of mitochondria by K+ efflux and subsequent intracellular disequilibrium. Thus, mitochondria and NLRP3 machinery appear to be closely interwoven at multiple levels.

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Acknowledgements

This study was supported by Bio & Medical Technology Development Program Fund of the National Research Foundation (NRF-2015M3A9B6073846, NRF-2015M3A9B6073856), and the NRF grant (NRF-2013R1A2A2A01067985). M-SL is the recipient of the Global Research Laboratory Grant of the National Research Foundation of Korea (K21004000003-12A0500-00310) and the Ulsan National Institute of Science and Technology Research Fund (2014M3A9D8034459).

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  1. Department of Microbiology and Immunology, BK 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Korea

    Je-Wook Yu

  2. Severance Biomedical Science Institute and Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea

    Myung-Shik Lee

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Yu, JW., Lee, MS. Mitochondria and the NLRP3 inflammasome: physiological and pathological relevance. Arch. Pharm. Res. 39, 1503–1518 (2016). https://doi.org/10.1007/s12272-016-0827-4

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