Ma Shijie, Zhao Yurong, Sun Jianwei, Mu Peiqiang, Deng Yiqun
Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, China.
Key Laboratory of Zoonosis of Ministry of Agriculture, South China Agricultural University, Guangzhou, China.
Front Pharmacol. 2018 Jan 5;8:954. doi: 10.3389/fphar.2017.00954. eCollection 2017.
T-2 toxin is one of the type A trichothecenes produced mainly by the genus. Due to its broad distribution and highly toxic nature, it is of great concern as a threat to human health and animal breeding. In addition to its ribotoxic effects, T-2 toxin exposure leads to mitochondrial dysfunction, reactive oxygen species (ROS) accumulation and eventually cell apoptosis. We observed that mitochondrial biogenesis is highly activated in animal cells exposed to T-2 toxin, probably in response to the short-term toxic effects of T-2 toxin. However, the molecular mechanisms of T-2 toxin-induced mitochondrial biogenesis remain unclear. In this study, we investigated the regulatory mechanism of key factors in the ROS production and mitochondrial biogenesis that were elicited by T-2 toxin in HepG2 and HEK293T cells. Low dosages of T-2 toxin significantly increased the levels of both mitochondrial biogenesis and ROS. This increase was linked to the upregulation of SIRT1, which is controlled by miR-449a, whose expression was strongly inhibited by T-2 toxin treatment. In addition, we found that T-2 toxin-induced mitochondrial biogenesis resulted from SIRT1-dependent PGC-1α deacetylation. The accumulation of PGC-1α deacetylation, mediated by high SIRT1 levels in T-2 toxin-treated cells, activated the expression of many genes involved in mitochondrial biogenesis. Together, these data indicated that the miR449a/SIRT1/deacetylated PGC-1α axis plays an essential role in the ability of moderate concentrations of T-2 toxin to stimulate mitochondrial biogenesis and ROS production.
T-2毒素是主要由该属产生的A型单端孢霉烯族毒素之一。由于其分布广泛且毒性极强，作为对人类健康和动物养殖的威胁，备受关注。除了其核糖毒性作用外，接触T-2毒素会导致线粒体功能障碍、活性氧（ROS）积累并最终导致细胞凋亡。我们观察到，在接触T-2毒素的动物细胞中，线粒体生物合成被高度激活，这可能是对T-2毒素短期毒性作用的反应。然而，T-2毒素诱导线粒体生物合成的分子机制仍不清楚。在本研究中，我们调查了T-2毒素在HepG2和HEK293T细胞中引发的ROS产生和线粒体生物合成关键因子的调控机制。低剂量的T-2毒素显著增加了线粒体生物合成和ROS的水平。这种增加与SIRT1的上调有关，SIRT1受miR-449a调控，而T-2毒素处理强烈抑制了miR-449a的表达。此外，我们发现T-2毒素诱导的线粒体生物合成是由SIRT1依赖的PGC-1α去乙酰化引起的。在T-2毒素处理的细胞中，高SIRT1水平介导的PGC-1α去乙酰化积累激活了许多参与线粒体生物合成的基因的表达。总之，这些数据表明，miR449a/SIRT1/去乙酰化的PGC-1α轴在中等浓度的T-2毒素刺激线粒体生物合成和ROS产生的能力中起重要作用。
