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J Biol Chem. 2015 Nov 6;290(45):27425-37. doi: 10.1074/jbc.M115.667063. Epub 2015 Sep 28.

Rotenone-induced Impairment of Mitochondrial Electron Transport Chain Confers a Selective Priming Signal for NLRP3 Inflammasome Activation.

Author information

1
From the Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea.
2
From the Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea Jewookyu@yuhs.ac.

Abstract

Mitochondrial dysfunction is considered crucial for NLRP3 inflammasome activation partly through its release of mitochondrial toxic products, such as mitochondrial reactive oxygen species (mROS)(2) and mitochondrial DNA (mtDNA). Although previous studies have shown that classical NLRP3-activating stimulations lead to mROS generation and mtDNA release, it remains poorly understood whether and how mitochondrial damage-derived factors may contribute to NLRP3 inflammasome activation. Here, we demonstrate that impairment of the mitochondrial electron transport chain by rotenone primes NLRP3 inflammasome activation only upon costimulation with ATP and not with nigericin or alum. Rotenone-induced priming of NLRP3 in the presence of ATP triggered the formation of specklike NLRP3 or ASC aggregates and the association of NLRP3 with ASC, resulting in NLRP3-dependent caspase-1 activation. Mechanistically, rotenone confers a priming signal for NLRP3 inflammasome activation only in the context of aberrant high-grade, but not low-grade, mROS production and mitochondrial hyperpolarization. By contrast, rotenone/ATP-mediated mtDNA release and mitochondrial depolarization are likely to be merely an indication of mitochondrial damage rather than triggering factors for NLRP3 inflammasome activation. Our results provide a molecular insight into the selective contribution made by mitochondrial dysfunction to the NLRP3 inflammasome pathway.

KEYWORDS:

NLRP3; inflammasome; innate immunity; mitochondrial dysfunction; mitochondrial respiratory chain complex; reactive oxygen species (ROS)

PMID:
26416893
PMCID:
PMC4646374
DOI:
10.1074/jbc.M115.667063
[Indexed for MEDLINE]
Free PMC Article

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