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Open Access Research article

Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines

Amarjargal Dashdorj1, Jyothi KR1, Sangbin Lim1, Ara Jo1, Minh Nam Nguyen1, Joohun Ha1, Kyung-Sik Yoon1, Hyo Jong Kim2, Jae-Hoon Park3, Michael P Murphy4 and Sung Soo Kim1*

Author Affiliations

1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea

2 Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea

3 Department of Pathology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea

4 MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK

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BMC Medicine 2013, 11:178  doi:10.1186/1741-7015-11-178

Published: 6 August 2013

Abstract

Background

MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation.

Methods

Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.

Results

Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.

Conclusion

Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

Keywords:
Dextran sulfate sodium; Interleukin-1 beta; Interleukin-18; MitoQ;NLRP-3 inflammasome; Reactive oxygen species