MCU promotes oxidative stress by regulating SIRT3 to destroy the pancreatic duct epithelial cytoskeleton: In vivo and in vitro hypertriglyceridema-induced pancreatitis

Background The pathogenesis of hypertriglyceridema-induced pancreatitis (HTGP) is complex and not fully understood. The purpose of this study was to investigate the molecular mechanism of MCU in HTGP. Methods We observed the expression levels of MCU and SIRT3 in both in vivo and in vitro HTGP models, and after intervention with RR, an active inhibitor of MCU, and 3-TYP, an active inhibitor of SIRT3, changes in mitochondrial calcium ions, oxidative stress-related indices, the microfilament cytoskeleton, and monolayer cell permeability were detected. Results In vivo and in vitro experiments revealed the upregulation of MCU and downregulation of SIRT3 in caerulein-treated HPDE6-C7 cells and mice, along with increased mitochondrial calcium accumulation, increased ROS and MDA, decreased GSH, destruction of the microfilament cytoskeleton, and increased monolayer permeability. During in vitro experiments, intervention with RR, an active inhibitor of MCU, reversed the above changes, whereas intervention with 3-TYP, an active inhibitor of SIRT3, further exacerbated the above changes. Conclusions MCU may be involved in the pathogenesis of AP by inhibiting the expression of SIRT3, resulting in increased oxidative stress and destruction of the microfilament cytoskeleton and PDMB functions.