MRG15 promotes cell apoptosis through inhibition of mitophagy in hyperlipidemic acute pancreatitis.

Abstract

Hyperlipidemia is a common cause of acute pancreatitis (AP), often leading to more severe clinical symptoms. The mortality factor 4-like protein 1 (MORF4L1, also called MRG15) plays a crucial role in regulating lipid metabolism. Therefore, this study aimed to explore the mechanism of MRG15 in hyperlipidemic acute pancreatitis (HAP). Mendelian randomization, transcriptome analysis, and single-cell analysis were employed to explore the association between MRG15 and AP by utilizing publicly available databases. In vivo, hypertriglyceridemia mouse models were created by intraperitoneal injection of P407 or using APOE-deficient mice. Subsequently, the HAP model was induced by cerulean. In vitro, a cell model of HAP was established by initially exposing cells to palmitic acid to simulate a high-fat environment, followed by cerulein treatment. Subsequently, MRG15-related indicators were measured. Through Mendelian randomization, it was discovered that there is a positive correlation between genetic expression of MRG15 and the risk of AP. Transcriptome and single-cell analysis revealed that elevated MRG15 expression in AP contributes to lipid metabolism disorders and the activation of apoptosis pathways in pancreatic acinar cells. MRG15 is found to be significantly upregulated in cases of HAP. Knocking down MRG15 led to an increase in mitophagy and a decrease in apoptosis in pancreatic cells, and this effect was reversed when the mitochondrial Tu translation elongation factor (TUFM) was simultaneously knocked down. MRG15 inhibits mitophagy by degrading TUFM, ultimately promoting cell apoptosis and worsening the progression of HAP.