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.
Highlights
Intestinal ischemia reperfusion (I/R) is one of the most common, critical events due to acute mesenteric ischemia, hemorrhagic shock, trauma, sepsis, burns, and surgical procedures[1]
We investigated the role of MitoQ following intestinal I/R injury, and our results suggest that MitoQ enhances intestinal barrier integrity by activating the Nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway and preventing damage to mitochondrial DNA (mtDNA) from oxidative stress, which was associated with stabilization of mitochondrial transcription factor A (TFAM) and a decrease in mitochondrial ROS production
Upon examination of histological changes by HE staining, pretreatment with MitoQ preserved the integrity of morphological structures, and alleviated both neutrophil infiltration and hemorrhage in the I/R-injured intestine compared to the I/R group, illustrating the protective effect of MitoQ preconditioning on I/R-injured intestinal mucosal epithelial damage (Fig. 1b)
Summary
Intestinal ischemia reperfusion (I/R) is one of the most common, critical events due to acute mesenteric ischemia, hemorrhagic shock, trauma, sepsis, burns, and surgical procedures[1]. Intestinal I/R increases intestinal permeability and demolishes mucosal barrier function[2]. Damaging or overwhelming the intestinal barrier provides route for viable bacteria and their antigens from the luminal environment to enter the circulation and mesenteric lymph, leading to systemic response syndrome (SIRS) or multiple organ dysfunction syndrome (MODS)[3]. Maintenance or repair of the intestinal mucosal barrier is, a key target for I/R-associated rescue in critically ill patients. Oxidative stress plays a critical role during the pathogenesis of intestinal I/R. Previous research has suggested that the imbalance between oxygen delivery and oxygen demand induces production of reactive oxygen species
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