The mitochondrially targeted antioxidant MitoQ protects the intestinal barrier by ameliorating mitochondrial DNA damage via the Nrf2/ARE signaling pathway

Abstract

Disruption of the mucosal barrier following intestinal ischemia reperfusion (I/R) is life threatening in clinical practice. Mitochondrial dysfunction and oxidative stress significantly contribute to the early phase of I/R injury and amplify the inflammatory response. MitoQ is a mitochondrially targeted antioxidant that exerts protective effects following I/R injury. In the present study, we aimed to determine whether and how MitoQ protects intestinal epithelial cells (IECs) from I/R injury. In both in vivo and in vitro studies, we found that MitoQ pretreatment downregulated I/R-induced oxidative stress and stabilized the intestinal barrier, as evidenced by MitoQ-treated I/R mice exhibiting attenuated intestinal hyperpermeability, inflammatory response, epithelial apoptosis, and tight junction damage compared to controls. Mechanistically, I/R elevated mitochondrial 8-hydroxyguanine content, reduced mitochondrial DNA (mtDNA) copy number and mRNA transcription levels, and induced mitochondrial disruption in IECs. However, MitoQ pretreatment dramatically inhibited these deleterious effects. mtDNA depletion alone was sufficient to induce apoptosis and mitochondrial dysfunction of IECs. Mitochondrial transcription factor A (TFAM), a key activator of mitochondrial transcription, was significantly reduced during I/R injury, a phenomenon that was prevented by MitoQ treatment. Furthermore, we observed that thee protective properties of MitoQ were affected by upregulation of cellular antioxidant genes, including HO-1, NQO-1, and γ-GCLC. Transfection with Nrf2 siRNA in IECs exposed to hypoxia/reperfusion conditions partially blocked the effects of MitoQ on mtDNA damage and mitochondrial oxidative stress. In conclusion, our data suggest that MitoQ exerts protective effect on I/R-induced intestinal barrier dysfunction.

MitoQ Modulates Lipopolysaccharide-Induced Intestinal Barrier Dysfunction via Regulating Nrf2 Signaling

“…4 μm of paraffin sections were stained by hematoxylin and eosin (H&E) for light microscopy. Histological score of intestine injury was assessed according to the instructions as previously described [11]. Histological score for every section was evaluated blindly.…”

“…Because of MitoQ's strong antioxidant ability, MitoQ has been suggested to play a protective role in a variety of diseases, including ischemia reperfusion (IR) and liver fibrosis [9,10]. Particularly, Hu et al [11] recently indicated that MitoQ could alleviate the intestinal injury via activating nuclear factor E2-related factor 2 (Nrf2) signaling following IR. Therefore, we hypothesized that MitoQ can protect against the sepsis-induced intestinal injury.…”

“…Mediators of Inflammation [20]. Hu et al [11] recently demonstrated that mitochondrial integrity was damaged in critical ill patients, and they further showed that mitochondria-targeted antioxidants significantly protected against ischemia-/reperfusion-associated organ injuries. They also indicated that MitoQ could inhibit the activities of respiratory chain complexes I, III, and IV and restored the mitochondrial ATP production.…”

“…Nrf2 signaling plays an irreplaceable factor in oxidative stress-induced tissue injures and activation of Nrf2 pathway protected cells from oxidative insults [11,25]. Upon the activation of oxidative insults, Nrf2 translocates from cytoplasm to nucleus and subsequently activates downstream Mediators of Inflammation antioxidant genes [26].…”

Bryostatin‐1 ameliorated experimental colitis in Il‐10−/− Mice by protecting the intestinal barrier and limiting immune dysfunction

“…Activated Nrf2 signalling shows strong antiapoptotic and antioxidant effects, especially in alleviating intestinal epithelial cell apoptosis during intestinal injury in recent studies. [34][35][36] In the present work, the increased expression of Nrf2 and its downstream factor HO-1 in the Bry-1-treated Il-10 −/− mice may partly explain the protective role of Bry-1 in Il-10 −/− mice.…”