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

BMC Med. 2013 Aug 6;11:178. doi: 10.1186/1741-7015-11-178.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use*
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / physiology
  • Cells, Cultured
  • Colitis / drug therapy*
  • Colitis / metabolism
  • Colitis / pathology
  • Disease Models, Animal
  • Drug Delivery Systems / methods
  • Female
  • Humans
  • Inflammasomes / antagonists & inhibitors*
  • Inflammasomes / physiology
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / physiology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Organophosphorus Compounds / administration & dosage*
  • Organophosphorus Compounds / therapeutic use
  • Reactive Oxygen Species / metabolism
  • Ubiquinone / administration & dosage
  • Ubiquinone / analogs & derivatives*
  • Ubiquinone / therapeutic use

Substances

  • 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