MCU-Mediated SIRT3 Inhibition Drives Oxidative Stress-Induced Cytoskeletal Disruption in Pancreatic Ductal Epithelium: A Mechanism of Hypertriglyceridemic Acute Pancreatitis.

PURPOSE: The pathogenesis of hypertriglyceridemia -induced pancreatitis (HTGP) is complex and not fully understood. The purpose of this study was to investigate the molecular mechanism of the mitochondrial Ca(2+) uniporter (MCU) in HTGP. METHODS: We observed the expression levels of MCU and silent information regulator 3 (SIRT3) in both in vivo and in vitro HTGP models, and after intervention with ruthenium red (RR), an active inhibitor of MCU, and 3-(1H-1,2,3-triazol-4-yl) pyridine (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 reactive oxygen species (ROS) and malondialdehyde (MDA) levels, decreased gamma-glutamylcysteine (GSH) levels, 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. CONCLUSION: 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 pancreatic ductal mucosal barrier (PDMB) functions.