Deoxynivalenol induced intestinal barrier injury, mitochondrial dysfunction and calcium overload by inositol 1,4,5-triphosphate receptors (IP3Rs)-mitochondrial calcium uniporter (MCU) calcium axis

Deoxynivalenol (DON) contamination is widespread in crops and could easily cause intestinal injury, which brings hazards to animals. Mitochondria are considered as an important target of DON, nevertheless, the mechanism is still unclear. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) have gained arousing interest and are recognized as critical signaling hubs that control calcium signaling transduction between ER and mitochondria. This study aims to investigate the effects of DON on intestinal barrier, mitochondria, MAMs and inositol 1,4,5-triphosphate receptors (IP3Rs)-mitochondrial calcium uniporter (MCU) calcium axis in piglets and porcine intestinal epithelial cells (IPEC-J2). Furthermore, inhibition of IP3Rs or MCU was used to explore whether IP3Rs-MCU axis of MAMs was involved in the mitochondria dysfunction and intestinal epithelium barrier injury induced by DON in IPEC-J2. The data showed that DON induced intestinal barrier injury, mitochondrial dysfunction and ERS in piglets' jejunum and IPEC-J2. Moreover, DON increased MAMs by upregulating the protein level of Mitofusin 2 (Mfn2), increasing the percentage of mitochondria with MAMs/total mitochondria and the ratio of MAMs length/mitochondrial perimeter and shortening the distance between mitochondria and ER of MAMs. Importantly, DON influenced IP3Rs-glucose-regulated protein 75 (GRP75) voltage -dependent anion channel 1 (VDAC1)-MCU calcium axis by increasing the protein levels of GRP75 and MCU and the interaction of VDAC1-GRP75-IP3Rs complex, which in turn induced mitochondrial calcium overload. Furthermore, inhibition of IP3Rs or MCU alleviated DON -induced intestinal epithelium barrier injury, mitochondrial dysfunction and mitochondrial calcium overload of IPEC-J2. The current investigation proposed that DON induced intestinal injury, mitochondrial dysfunction and calcium overload via IP3Rs-GRP75-VDAC1- MCU calcium axis.