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Rotenone-induced Impairment of Mitochondrial Electron Transport Chain Confers a Selective Priming Signal for NLRP3 Inflammasome Activation
Open accessAbstract
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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“Several studies have shown that inhibition of mitochondrial complex I by rotenone or of complex III by antimycin A induces robust ROS production by mitochondria, which is sufficient to drive NLRP3 inflammasome activation.39, 40”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [40]
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K + Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria
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Mitochondrial ROS promote macrophage pyroptosis by inducing GSDMD oxidation
Wang, Y., Shi, P., Chen, Q., Huang, Z., Zou, D., Zhang, J., Gao, X., & Lin, Z. (2019) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjz020 · Cited by 365
Metadata
- Authors
- Won, J.-H., Park, S., Hong, S., Son, S., & Yu, J.-W.
- Affiliations
- Yonsei University (KR)
- Corresponding author
- 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)
- 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
- 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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