Fan Peng, Deng Huidan, Wang Ya, Ren Zhihua, Deng Junliang
Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, China.
Int J Mol Sci. 2025 Aug 25;26(17):8222. doi: 10.3390/ijms26178222.
Deoxynivalenol (DON), a global mycotoxin contaminant, induces immunotoxicity in swine and humans by disrupting mitochondrial membrane integrity and activating mitophagy. SIRT3 plays an important role in regulating cell metabolism and various diseases. It also regulates apoptosis (caused by DON) by regulating the mitophagy pathway, but this pathway has not been studied yet. Gene knockout and overexpression of SIRT3 were performed for proteomics and acetylation modification. Therefore, in this study, PAM cells were selected as an in vitro model of DON (1.1 μg/mL) exposure for 24 h. The results showed that the knockout impaired mitochondrial antioxidant function, whereas overexpression improves damage stimulation. DON can also affect the metabolism of immune pathways, but SIRT3 can enrich these substances' metabolism. The results of the acetylation modification analysis showed that knockout affected the mRNA metabolism and others, while overexpression affected apoptosis and others. DON exposure caused fatty acid degradation, and altered MAPK signaling pathway. Knockout and overexpression of SIRT3 under DON exposure were enriched in PPAR, Ferroptosis pathway. Overexpression attenuated DON-induced mitophagy by reducing cellular ROS, as well as the expression of LC3, P62 and PINK1/Parkin. Finally, SIRT3 reduced cell apoptosis by reducing the expression of BAX and CASP3 and increasing the expression of BCL-2. These results indicated that SIRT3 could alleviate DON-induced cell damage by reducing apoptosis through the mitophagy pathway.
脱氧雪腐镰刀菌烯醇（DON）是一种全球范围内的霉菌毒素污染物，通过破坏线粒体膜完整性和激活线粒体自噬，在猪和人类中诱导免疫毒性。SIRT3在调节细胞代谢和各种疾病中发挥着重要作用。它还通过调节线粒体自噬途径来调节（由DON引起的）细胞凋亡，但该途径尚未得到研究。通过蛋白质组学和乙酰化修饰对SIRT3进行基因敲除和过表达。因此，在本研究中，选择PAM细胞作为DON（1.1μg/mL）体外暴露24小时的模型。结果表明，敲除会损害线粒体抗氧化功能，而过表达则可改善损伤刺激。DON还可影响免疫途径的代谢，但SIRT3可使这些物质的代谢富集。乙酰化修饰分析结果表明，敲除影响mRNA代谢等，而过表达影响细胞凋亡等。DON暴露导致脂肪酸降解，并改变丝裂原活化蛋白激酶（MAPK）信号通路。在DON暴露下，SIRT3的敲除和过表达在过氧化物酶体增殖物激活受体（PPAR）、铁死亡途径中富集。过表达通过降低细胞活性氧（ROS）以及微管相关蛋白1轻链3（LC3）、p62和PTEN诱导激酶1/帕金蛋白（PINK1/Parkin）的表达，减弱了DON诱导的线粒体自噬。最后，SIRT3通过降低Bax和半胱天冬酶3（CASP3）的表达并增加B细胞淋巴瘤-2（BCL-2）的表达来减少细胞凋亡。这些结果表明，SIRT3可通过线粒体自噬途径减少细胞凋亡，从而减轻DON诱导的细胞损伤。
