动物细胞线粒体响应单端孢霉烯族霉菌毒素的分子机制

Ttrichothecenes (TRIs) are an important structural related mycotoxin family. TRIs consist of two subgroups, DON and T-2 as the representatives of group A and B, and mainly produced by Fusarium species. The contaminations of TRIs in food and crops are naturally and broadly happened, and thus difficult to be controlled. In-taking of TRIs results in various toxic effects, including reproductive toxicity, immunotoxicity and neurotoxicity. However, the molecular mechanisms of their cytotoxicity require to be further clarified. Our previous study discovered that T-2 toxin triggered apoptosis, mediated by mitochondrial pathway, and also induced compensatory mitochondrial proliferation. The molecular mechanism how mitochondria respond to TRIs remains unclear in animal cells. This project aims to reveal the mitochondrial responding mechanism induced by TRIs in different animal cells. In first, we would measure the mitochondrial morphology, energy metabolism, redox regulation in DON and T-2 toxin treated cells, and analyze its differences between the two groups in different cell lines. Secondly, based on the analysis, the main signaling pathway and key target proteins of TRIs would be identified by mitochondrial proteomics. Finally, the common mechanism of animal mitochondrion responding to TRIs would be further addressed and the molecular mechanism would be clarified. The study has a great potential to answer the important linkage between mitochondria physiology and TRIs’ toxicity. The clarification of the molecular toxicological mechanism of TRIs mediated by the alteration of mitochondria in animal cells, would update the scientific theory of TRIs’ cytotoxicity, and furtherly provide new ways for TRIs defense and detoxication.

单端孢霉烯族霉菌毒素(Trichothecenes,TRIs)是由禾谷镰刀菌等真菌产生的一类结构相似的重要霉菌毒素。该类毒素自然发生、污染广泛、难以控制。已有报道表明TRIs具有生殖毒性、免疫毒性和神经毒性等多种毒性作用。然而，其分子毒理机制仍有待完善。本课题组前期研究发现，TRIs A族代表T-2毒素可诱发线粒体途径的细胞凋亡，同时可诱导线粒体的代偿性增生，但线粒体对其响应的具体分子机制仍不清楚。本项目拟从线粒体形态结构、能量代谢状态、氧化还原调控等角度进一步系统分析不同细胞系的线粒体对TRIs的响应特征，并比较A、B两族毒素之间和不同细胞系之间的差异。进一步通过线粒体蛋白组学筛选鉴定TRIs作用的主要信号通路及其关键靶蛋白，阐明其作用机制，探究TRIs在动物细胞内引发的线粒体响应的普遍规律。研究成果可进一步完善TRIs的分子毒理机制，同时为TRIs毒素的防御和减毒等提供新思路。

单端孢霉烯族霉菌毒素(TRIs)是由禾谷镰刀菌等真菌产生的一类结构相似的霉菌毒素。该类毒素自然发生、污染广泛、难以控制。T-2毒素是TRIs中毒性最强的毒素之一。已有研究表明,线粒体是该毒素的重要靶点，但分子机制仍不清楚。本研究发现T-2毒素处理下的普遍性线粒体代偿性增生。其分子机制为：T-2毒素通过抑制miR-449a的表达，上调线粒体增生关键因子SIRT1的表达，降低线粒体合成核心调控因子PGC1α的乙酰化水平，保持PGC1α的活性，从而诱导线粒体增生。基于上述研究，提出了T-2毒素对线粒体功能调控的新机理：一方面，T-2毒素通过诱导活性氧等引起细胞的DNA损伤和细胞凋亡；另一方面，细胞通过代偿性的线粒体增生，利用线粒体能量补偿，从而减轻T-2毒素对细胞的损伤，修正了T-2毒素通过线粒体途径促细胞凋亡的单一认识。项目研究内容发表SCI研究论文3篇。项目负责人在项目执行期间入选国家高层次人才特殊支持计划领军人才，培养博士生2人，硕士生3人。