Diminution of HSP75 disrupts intestinal epithelial barrier by inciting mPTP opening in ulcerative colitis

Ulcerative colitis is an idiopathic, chronic inflammatory disorder. The disruption of intestinal epithelial barrier caused by excessive apoptosis of intestinal epithelial cells is a pivotal factor in the etiology and pathology. The mitochondrial pathway is the most significant apoptosis mode of intestinal epithelial cells, which was regulated by the mitochondrial permeability transition pore(mPTP). However, the precise mechanism remains elusive. As a crucial molecule in combating stress and maintaining mitochondrial homeostasis, the heat shock protein 75(HSP75) may play a vital role in regulating the openness of the mPTP. In our research, we ascertained that HSP75 was significantly diminished in the intestinal mucosal of UC patients and experimental colitis mice, concomitantly with the disruption of intestinal epithelial barrier. Furthermore, a negative correlation between HSP75 and the openness of mPTP, mitochondrial-driven apoptosis, and disruption of intestinal epithelial barrier has been demonstrated in vivo and vitro. Secondly, HSP75 level is negatively correlated with the expression of ANT, VDAC, and PiC, which considered to be the components of mPTP. However, the CypD is unaffected by HSP75. Finally, HSP75 altered the synthesis of ANT, VDAC, PiC and the acetylation modification of ANT, but there is no direct interaction between HSP75 and mPTP component proteins. In conclusion, the present study demonstrated that HSP75 significantly decreased in the intestinal mucosa of UC, and preliminarily revealed a novel mechanism of HSP75 regulating the synthesis and openness of mPTP in the intestinal epithelial cells(IECs) of UC, suggesting that the targeted intestinal mucosa supplementation of HSP75 is anticipated to reverse the pathological process.