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

Authors
 Ji-Hee Won  ;  Sangjun Park  ;  Sujeong Hong  ;  Seunghwan Son  ;  Je-Wook Yu 
Citation
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.290(45) : 27425-27437, 2015 
Journal Title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN
 0021-9258 
Issue Date
2015
MeSH
Adenosine Triphosphate/metabolism ; Animals ; Carrier Proteins/genetics ; Carrier Proteins/metabolism* ; Caspase 1/metabolism ; Cells, Cultured ; DNA, Mitochondrial/metabolism ; Electron Transport/drug effects ; Electron Transport Chain Complex Proteins/antagonists & inhibitors* ; Inflammasomes/drug effects* ; Inflammasomes/metabolism* ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/drug effects* ; Mitochondria/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein ; Reactive Oxygen Species/metabolism ; Rotenone/pharmacology* ; Uncoupling Agents/pharmacology*
Keywords
NLRP3 ; inflammasome ; innate immunity ; mitochondrial dysfunction ; mitochondrial respiratory chain complex ; reactive oxygen species (ROS)
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.
Files in This Item:
T201504383.pdf Download
DOI
10.1074/jbc.M115.667063
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Won, Ji Hee(원지희)
Yu, Je Wook(유제욱) ORCID logo https://orcid.org/0000-0001-5943-4071
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/156700
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