Department of Physiology, Faculty of Pharmacy, University of Valencia, Spain.
Oxidative Stress and Cancer Laboratory, Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif sur Yvette, France.
Redox Biol. 2022 Oct;56:102423. doi: 10.1016/j.redox.2022.102423. Epub 2022 Aug 20.
Mitochondrial dysfunction is a key contributor to necroptosis. We have investigated the contribution of p53, sulfiredoxin, and mitochondrial peroxiredoxin 3 to necroptosis in acute pancreatitis. Late during the course of pancreatitis, p53 was localized in mitochondria of pancreatic cells undergoing necroptosis. In mice lacking p53, necroptosis was absent, and levels of PGC-1α, peroxiredoxin 3 and sulfiredoxin were upregulated. During the early stage of pancreatitis, prior to necroptosis, sulfiredoxin was upregulated and localized into mitochondria. In mice lacking sulfiredoxin with pancreatitis, peroxiredoxin 3 was hyperoxidized, p53 localized in mitochondria, and necroptosis occurred faster; which was prevented by Mito-TEMPO. In obese mice, necroptosis occurred in pancreas and adipose tissue. The lack of p53 up-regulated sulfiredoxin and abrogated necroptosis in pancreas and adipose tissue from obese mice. We describe here a positive feedback between mitochondrial HO and p53 that downregulates sulfiredoxin and peroxiredoxin 3 leading to necroptosis in inflammation and obesity.
线粒体功能障碍是细胞发生坏死性凋亡的关键因素。本研究旨在探讨 p53、硫氧还蛋白和线粒体过氧化物酶 3 对急性胰腺炎中坏死性凋亡的作用。在胰腺炎后期，p53 定位于发生坏死性凋亡的胰腺细胞线粒体中。在 p53 缺失的小鼠中，坏死性凋亡消失，PGC-1α、过氧化物酶 3 和硫氧还蛋白的水平上调。在胰腺炎的早期，坏死性凋亡发生之前，硫氧还蛋白上调并定位于线粒体。在发生胰腺炎的硫氧还蛋白缺失的小鼠中，过氧化物酶 3 过度氧化，p53 定位于线粒体，坏死性凋亡发生更快；这可以通过 Mito-TEMPO 预防。在肥胖小鼠中，胰腺和脂肪组织发生坏死性凋亡。p53 的缺失增加了硫氧还蛋白的表达并阻止了肥胖小鼠胰腺和脂肪组织中的坏死性凋亡。本研究描述了线粒体 HO 和 p53 之间的正反馈，下调了硫氧还蛋白和过氧化物酶 3，导致炎症和肥胖中的坏死性凋亡。
