Citrinin-Induced Intestinal Onset of Pyroptosis via the IP3R1–GRP75–VDAC1 Complex-Mediated Mitochondrial Oxidative Stress

Abstract

Citrinin (CTN) is commonly found in animal feed and stored grains and poses a serious threat to human and animal health. Formation of the IP3R1–GRP75–VDAC1 complex has been shown to play a key role in intestinal defense against harmful stimuli, but the mechanism of its action in CTN-exposure-induced enterotoxicity is not clear. Therefore, the aim of this study was to investigate the role of the IP3R1–GRP75–VDAC1 complex in CTN-exposure-induced intestinal and IPEC-J2 monolayer cell damage in mice. It was shown that CTN exposure triggered intestinal cell pyroptosis and increased IP3R1–GRP75–VDAC1 complex formation as well as mitochondrial levels of calcium ions and mitochondrial reactive oxygen species (mtROS). And mtROS is considered to be a key factor in cellular pyroptosis. Therefore, the removal of mtROS by using Mito-Tempo was found to attenuate CTN-exposure-induced cellular pyroptosis but failed to attenuate mitochondrial calcium ion overload. However, silencing of GRP75 alleviated CTN-exposure-induced increases in the level of mtROS, mitochondrial calcium ions, and subsequent cellular pyroptosis. Therefore, this study confirms that CTN exposure induces cellular juxtaposition in intestinal tissues and points out that mitochondrial oxidative stress mediated by the IP3R1–GRP75–VDAC1 complex is a key mechanism by which CTN exposure triggers intestinal cellular pyroptosis.