Cited by 142Inflammasome and immune disordersImmune Response and InflammationMitochondrial Function and Pathology

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

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Won, Ji-Hee, Park, Sangjun, Hong, Sujeong, Son, Seunghwan, Yu, Je-Wook·2015·Journal of Biological Chemistry

DOI 10.1074/jbc.m115.667063PMC PMC4646374

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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 2The abbreviations used are: mROSmitochondrial reactive oxygen speciesmtDNAmitochondrial DNABMDMbone marrow-derived macrophageETCelectron transport chainMPTmitochondrial permeability transitionCCCPcarbonyl cyanide m-chlorophenylhydrazoneNACN-acetyl-l-cysteineZ-benzyloxycarbonyl-fmkfluoromethyl ketone. 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.

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Authors: Won, J.-H., Park, S., Hong, S., Son, S., & Yu, J.-W.
Affiliations: Yonsei University (KR)
Corresponding author: Yu, Je-Wook
ORCID: Son, Seunghwan
Yu, Je-Wook
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2015-11
Volume: 290
Issue: 45
Pages: 27425-27437
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m115.667063
PMC: PMC4646374
OpenAlex: W2269000464
Cited by: 142
References: 34
Citations by year: 2026: 18 · 2025: 16 · 2024: 9 · 2023: 18 · 2022: 12 · 2021: 14 · 2020: 12 · 2019: 15 · 2018: 11 · 2017: 12 · 2016: 5
FWCI: 4.05
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 1774 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
Funders: National Research Foundation
National Research Foundation of Korea (2013R1A2A2A01067985, 2012R1A1A2041532, 2014R1A4A 1008625)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords: NLRP3 inflammasome, rotenone, mitochondrial electron transport chain, mitochondrial dysfunction, mitochondrial reactive oxygen species, mitochondrial DNA release, mitochondrial hyperpolarization, mitochondrial depolarization, caspase-1 activation, ASC, bone marrow-derived macrophages, inflammasome activation
MeSH terms: NLR Family, Pyrin Domain-Containing 3 Protein, Adenosine Triphosphate, Animals, Carrier Proteins, Cells, Cultured, DNA, Mitochondrial, Electron Transport, Mice, Inbred C57BL, Mitochondria, Rotenone, Uncoupling Agents, Reactive Oxygen Species, Mice, Knockout, Caspase 1, Electron Transport Chain Complex Proteins, Mice, Inflammasomes

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

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