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PMID: 23915129 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

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

BMC medicine ·Vol. 11 ·2013-08-06 ·Pages 178

Dashdorj A, Jyothi KR, Lim S, Jo A, Nguyen MN, Ha J, Yoon KS, Kim HJ, Park JH, Murphy MP, Kim SS

Abstract

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. 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. 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. 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.

MeSH Terms
Animals Antioxidants/pharmacology,therapeutic use Carrier Proteins/antagonists & inhibitors,physiology Cells, Cultured Colitis/drug therapy,metabolism,pathology Disease Models, Animal Drug Delivery Systems/methods Female Humans Inflammasomes/antagonists & inhibitors,physiology Inflammation Mediators/antagonists & inhibitors,physiology Male Mice Mice, Inbred BALB C Mitochondria/drug effects,metabolism,pathology NLR Family, Pyrin Domain-Containing 3 Protein Organophosphorus Compounds/administration & dosage,therapeutic use Reactive Oxygen Species/metabolism Ubiquinone/administration & dosage,analogs & derivatives,therapeutic use
Chemicals
10-(6'-ubiquinonyl)decyltriphenylphosphonium bromide Antioxidants Carrier Proteins Inflammasomes Inflammation Mediators NLR Family, Pyrin Domain-Containing 3 Protein Nlrp3 protein, mouse Organophosphorus Compounds Reactive Oxygen Species Ubiquinone
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Dashdorj Amarjargal
Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
Jyothi K R
Lim Sangbin
Jo Ara
Nguyen Minh Nam
Ha Joohun
Yoon Kyung-Sik
Kim Hyo Jong
Park Jae-Hoon
Murphy Michael P
Kim Sung Soo
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Article Info
Journal
BMC medicine
Abbr.
BMC Med
ISSN
1741-7015
DOI
10.1186/1741-7015-11-178
Published
2013-08-06
Epub
2013-00-06
Pages
178
Language
English
Region
England
NLM ID
101190723
PMCID
PMC3750576
Subset
IM
Grants
Medical Research Council · MC_U105663142 · United Kingdom
External Links
PubMed source DOI: 10.1186/1741-7015-11-178 PMC Full Text View journal details
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