T-2 toxin induces mitochondrial dysfunction in chondrocytes via the p53-cyclophilin D pathway.
T-2 toxin induces mitochondrial dysfunction in chondrocytes via the p53-cyclophilin D pathway.
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DOI：
10.1016/j.jhazmat.2023.133090
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发表时间：
2023-11
影响因子：
13.6
通讯作者：
Fang-fang Yu;Shui-yuan Yu;Lei Sun;Juan Zuo;Kang-ting Luo;Miao Wang;Xiao-Li Fu;Feng Zhang;Hui Huang;Guo-yu Zhou;Yan-jie Wang;Yue Ba
中科院分区：
文献类型：
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作者：
Fang-fang Yu;Shui-yuan Yu;Lei Sun;Juan Zuo;Kang-ting Luo;Miao Wang;Xiao-Li Fu;Feng Zhang;Hui Huang;Guo-yu Zhou;Yan-jie Wang;Yue Ba
大骨节病是一种以深部软骨细胞坏死为特征的地方性关节病，T-2毒素暴露已被证实是其病因。本研究探讨T-2毒素通过p53-亲环素D（CypD）途径诱导软骨细胞线粒体功能障碍的机制。来自GeneCards的T-2毒素反应基因显着富集了p53信号通路。我们证明了T-2毒素诱导的大鼠关节软骨和ATDC 5细胞中p53蛋白和p53-CypD复合物的上调。透射电镜显示T-2毒素诱导ATDC 5细胞线粒体结构受损。此外，它可以导致线粒体通透性转换孔（mPTP）的过度开放，降低线粒体膜电位，并增加ATDC 5细胞中活性氧的产生。p53抑制剂Pifithrin-α可减轻T-2毒素诱导的软骨细胞p53-CypD复合物增加和线粒体功能障碍，提示p53在T-2毒素诱导的线粒体功能障碍中起重要作用。在机制上，T-2毒素可以激活p53蛋白，其可以转移到线粒体膜并与CypD形成复合物。p53和CypD结合增加介导mPTP过度开放，改变线粒体膜通透性，并最终诱导软骨细胞线粒体功能障碍和凋亡。
Kashin–Beck disease is an endemic joint disease characterized by deep chondrocyte necrosis, and T-2 toxin exposure has been confirmed its etiology. This study investigated mechanism of T-2 toxin inducing mitochondrial dysfunction of chondrocytes through p53-cyclophilin D (CypD) pathway. The p53 signaling pathway was significantly enriched in T-2 toxin response genes from GeneCards. We demonstrated the upregulation of the p53 protein and p53-CypD complex in rat articular cartilage and ATDC5 cells induced by T-2 toxin. Transmission electron microscopy showed the damaged mitochondrial structure of ATDC5 cells induced by T-2 toxin. Furthermore, it can lead to overopening of the mitochondrial permeability transition pore (mPTP), decreased mitochondrial membrane potential, and increased reactive oxygen species generation in ATDC5 cells. Pifithrin-α, the p53 inhibitor, alleviated the increased p53-CypD complex and mitochondrial dysfunction of chondrocytes induced by T-2 toxin, suggesting that p53 played an important role in T-2 toxin-induced mitochondrial dysfunction. Mechanistically, T-2 toxin can activate the p53 protein, which can be transferred to the mitochondrial membrane and form a complex with CypD. The increased binding of p53 and CypD mediated the excessive opening of mPTP, changed mitochondrial membrane permeability, and ultimately induced mitochondrial dysfunction and apoptosis of chondrocytes.