Coenzyme Q0 Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages

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Title:	Coenzyme Q0 Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages
Authors:	Hseu, You-Cheng Tseng, Yu-Fang Pandey, Sudhir Shrestha, Sirjana Lin, Kai-Yuan Lin, Cheng-Wen Lee, Chuan-Chen Huang, Sheng-Teng Yang, Hsin-Ling
Contributors:	China Medical University Taiwan Asia University Taiwan China Medical University Taiwan China Medical University Taiwan China Medical University Taiwan Chi Mei Hospital Department of Biotechnology, Chia Nan University of Pharmacy & Science China Medical University Taiwan China Medical University Taiwan China Medical University Hospital - Taiwan
Keywords:	oxidative stress cell-death signal-transduction down-regulation ros generation kappa-b autophagy mitochondria cancer apoptosis
Date:	2022
Issue Date:	2023-12-11 14:04:21 (UTC+8)
Publisher:	HINDAWI LTD
Abstract:	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 beta 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 beta 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 beta expression in LPS/ATP-stimulated RAW264.7 macrophages suggesting that CoQ(0) inhibited ROS-mediated NLRP3 inflammasome activation and IL1 beta 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.
Relation:	Oxidative Medicine and Cellular Longevity, v.2022, Article ID 4266214
Appears in Collections:	[Dept. of Biotechnology (including master's program)] Periodical Articles

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