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

Dashdorj A, Jyothi KR, Lim S, Jo A, Nguyen MN, Ha J, Yoon KS, Kim HJ, Park JH, Murphy MP, Kim SS - BMC Med (2013)

Bottom Line: The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.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.

View Article: PubMed Central - HTML - PubMed

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

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.

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MitoQ attenuates mitochondrial alteration and oxidative damage during DSS-induced colitis. (A) Representative transmission electron micrographs of colon. The magnification is indicated. Similar histological profiles were seen in three separate colons per group. (B) Sections of colonic tissues were subjected to immunohistochemical analysis with an antibody against malondialdehyde. The magnification is indicated. (C) Sections of colonic tissues were subjected to immunohistochemical analysis with an antibody against 3-nitrotyrosine staining. The magnification is indicated.
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Figure 3: MitoQ attenuates mitochondrial alteration and oxidative damage during DSS-induced colitis. (A) Representative transmission electron micrographs of colon. The magnification is indicated. Similar histological profiles were seen in three separate colons per group. (B) Sections of colonic tissues were subjected to immunohistochemical analysis with an antibody against malondialdehyde. The magnification is indicated. (C) Sections of colonic tissues were subjected to immunohistochemical analysis with an antibody against 3-nitrotyrosine staining. The magnification is indicated.

Mentions: To demonstrate the effect of MitoQ on mitochondria during colitis, we first studied mitochondrial structural changes. Electron microscopy of the colon of control mice revealed good preservation of normal mitochondrial structure (Figure 3A, left). In colon tissue in DSS and DSS+dTPP-treated mice,the majority of mitochondria had alterations in size and matrix. In some mitochondria, the matrix totally disappeared and only the outer membrane remained. In others, the cristae were disorganized because of edema in the matrix (Figure 3A, middle). MitoQ treatment reduced the morphological and mitochondrial injury during colitis (Figure 3A, right). There was a significant increase of malondialdehyde formation (a marker of lipid peroxidation, brown staining) in the colon during colitis (Figure 3B, middle) and MitoQ dramatically reduced the malondialdehyde formation (Figure 3B, right). Colitis was also associated with increased mitochondrial nitrotyrosine formation in the colon, an index of peroxynitrate-mediated protein nitration (Figure 3C, middle). However, MitoQ was protective against nitrate damage of the colon during colitis, as shown in Figure 3C (right). These data reveal that MitoQ protects mitochondria and reduces oxidative damage in the colon of mice with DSS-induced colitis.


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

Dashdorj A, Jyothi KR, Lim S, Jo A, Nguyen MN, Ha J, Yoon KS, Kim HJ, Park JH, Murphy MP, Kim SS - BMC Med (2013)

MitoQ attenuates mitochondrial alteration and oxidative damage during DSS-induced colitis. (A) Representative transmission electron micrographs of colon. The magnification is indicated. Similar histological profiles were seen in three separate colons per group. (B) Sections of colonic tissues were subjected to immunohistochemical analysis with an antibody against malondialdehyde. The magnification is indicated. (C) Sections of colonic tissues were subjected to immunohistochemical analysis with an antibody against 3-nitrotyrosine staining. The magnification is indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750576&req=5

Figure 3: MitoQ attenuates mitochondrial alteration and oxidative damage during DSS-induced colitis. (A) Representative transmission electron micrographs of colon. The magnification is indicated. Similar histological profiles were seen in three separate colons per group. (B) Sections of colonic tissues were subjected to immunohistochemical analysis with an antibody against malondialdehyde. The magnification is indicated. (C) Sections of colonic tissues were subjected to immunohistochemical analysis with an antibody against 3-nitrotyrosine staining. The magnification is indicated.
Mentions: To demonstrate the effect of MitoQ on mitochondria during colitis, we first studied mitochondrial structural changes. Electron microscopy of the colon of control mice revealed good preservation of normal mitochondrial structure (Figure 3A, left). In colon tissue in DSS and DSS+dTPP-treated mice,the majority of mitochondria had alterations in size and matrix. In some mitochondria, the matrix totally disappeared and only the outer membrane remained. In others, the cristae were disorganized because of edema in the matrix (Figure 3A, middle). MitoQ treatment reduced the morphological and mitochondrial injury during colitis (Figure 3A, right). There was a significant increase of malondialdehyde formation (a marker of lipid peroxidation, brown staining) in the colon during colitis (Figure 3B, middle) and MitoQ dramatically reduced the malondialdehyde formation (Figure 3B, right). Colitis was also associated with increased mitochondrial nitrotyrosine formation in the colon, an index of peroxynitrate-mediated protein nitration (Figure 3C, middle). However, MitoQ was protective against nitrate damage of the colon during colitis, as shown in Figure 3C (right). These data reveal that MitoQ protects mitochondria and reduces oxidative damage in the colon of mice with DSS-induced colitis.

Bottom Line: The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.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.

View Article: PubMed Central - HTML - PubMed

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

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.

Show MeSH
Related in: MedlinePlus