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Coenzyme Q (CoQ) analogs with a variable number of isoprenoid units have exhibited as anti-inflammatory as well as antioxidant molecules. Using novel quinone derivative CoQ 0 (2,3-dimethoxy-5-methyl-1,4-benzoquinone, zero side chain isoprenoid), we studied its molecular activities against LPS/ATP-induced inflammation and redox imbalance in murine RAW264.7 macrophages. CoQ 0 's non- or subcytotoxic concentration suppressed the NLRP3 inflammasome and procaspase-1 activation, followed by downregulation of IL1 β expression in LPS/ATP-stimulated RAW264.7 macrophages. Similarly, treatment of CoQ 0 led to LC3-I/II accumulation and p62/SQSTM1 activation. An increase in the Beclin-1/Bcl-2 ratio and a decrease in the expression of phosphorylated PI3K/AKT, p70 S6 kinase, and mTOR showed that autophagy was activated. Besides, CoQ 0 increased Parkin protein to recruit damaged mitochondria and induced mitophagy in LPS/ATP-stimulated RAW264.7 macrophages. CoQ 0 inhibited LPS/ATP-stimulated ROS generation in RAW264.7 macrophages. Notably, when LPS/ATP-stimulated RAW264.7 macrophages were treated with CoQ 0 , Mito-TEMPO (a mitochondrial ROS inhibitor), or N -acetylcysteine (NAC, a ROS inhibitor), there was a significant reduction of LPS/ATP-stimulated NLRP3 inflammasome activation and IL1 β expression. Interestingly, treatment with CoQ 0 or Mito-TEMPO, but not NAC, significantly increased LPS/ATP-induced LC3-II accumulation indicating that mitophagy plays a key role in the regulation of CoQ 0 -inhibited NLRP3 inflammasome activation. Nrf2 knockdown significantly decreased IL1 β expression in LPS/ATP-stimulated RAW264.7 macrophages suggesting that CoQ 0 inhibited ROS-mediated NLRP3 inflammasome activation and IL1 β expression was suppressed due to the Nrf2 activation. Hence, this study showed that CoQ 0 might be a promising candidate for the therapeutics of inflammatory disorders due to its effective anti-inflammatory as well as antioxidant properties.

Competing Interests: The authors declare no conflict of interest.

Titel:	Coenzyme Q <subscript>0</subscript> Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages.
Autor/in / Beteiligte Person:	Hseu, YC ; Tseng, YF ; Pandey, S ; Shrestha, S ; Lin, KY ; Lin, CW ; Lee, CC ; Huang, ST ; Yang, HL
Link:	Full Text Finder (Volltext)
Zeitschrift:	Oxidative medicine and cellular longevity, Jg. 2022 (2022-01-07), S. 4266214
Veröffentlichung:	2011- : New York : Hindawi Pub. Corp. ; <i>Original Publication</i>: 2008-2010: Austin, TX : Landes Bioscience, 2022
Medientyp:	academicJournal
ISSN:	1942-0994 (electronic)
DOI:	10.1155/2022/4266214
Schlagwort:	Animals Humans Mice Transfection Ubiquinone pharmacology Adenosine Triphosphate metabolism Inflammasomes drug effects Lipopolysaccharides metabolism Macrophages metabolism Mitophagy immunology Ubiquinone therapeutic use
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Oxid Med Cell Longev] 2022 Jan 07; Vol. 2022, pp. 4266214. <i>Date of Electronic Publication: </i>2022 Jan 07 (<i>Print Publication: </i>2022). MeSH Terms: Adenosine Triphosphate / metabolism ; Inflammasomes / drug effects ; Lipopolysaccharides / metabolism ; Macrophages / metabolism ; Mitophagy / immunology ; Ubiquinone / therapeutic use ; Animals ; Humans ; Mice ; Transfection ; Ubiquinone / pharmacology References: J Biol Chem. 2002 Jun 21;277(25):22131-9. (PMID: 11940570) ; Circ Res. 2015 Jan 2;116(1):167-82. (PMID: 25323859) ; Front Immunol. 2013 Jul 08;4:167. (PMID: 23847614) ; Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2774-8. (PMID: 8610116) ; Free Radic Biol Med. 1999 Sep;27(5-6):612-6. (PMID: 10490282) ; Nature. 2006 Mar 9;440(7081):237-41. (PMID: 16407889) ; J Med Chem. 2020 Sep 24;63(18):10135-10157. (PMID: 32324396) ; J Biol Chem. 2011 Mar 18;286(11):9587-97. 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Coenzyme Q <subscript>0</subscript> Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages.