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An fusaric acid-based CRISPR library screen identifies MDH2 as a broad-spectrum regulator of Fusarium toxin-induced cell death

文献类型： 外文期刊

作者： Shi, Wei-Tao 1 ; Yao, Chun-Peng 2 ; Liu, Wen-Hua 1 ; Cao, Wan-Yi 1 ; Shao, Wei 3 ; Liao, Shen-Quan 4 ; Yu, Ting 1 ; Zhu, Qing-Feng 1 ; Chen, Zhuang 1 ; Zang, Ying-Jie 1 ; Farooq, Muhammad 1 ; Wei, Wen-Kang 1 ; Zhang, Xiao-Ai 1 ;

作者机构： 1.Guangdong Acad Agr Sci, Agrobiol Gene Res Ctr, State Key Lab Swine & Poultry Breeding Ind, Guangzhou 510640, Peoples R China

2.Guangdong Acad Agr Sci, Vegetable Res Inst, Guangdong Key Lab New Technol Res Vegetables, Guangzhou 510640, Peoples R China

3.Xinjiang Agr Univ, Coll Anim Sci, Urumqi 830052, Peoples R China

4.Guangdong Acad Agr Sci, Inst Anim Sci, Guangzhou 510640, Peoples R China

关键词： Fusaric acid; Fusarium toxin; CRISPR screening; MDH2; Cell death

期刊名称：JOURNAL OF HAZARDOUS MATERIALS （ 影响因子：11.3； 五年影响因子：12.4 ）

ISSN： 0304-3894

年卷期： 2024 年 480 卷

页码：

收录情况： SCI

摘要： Fusarium mycotoxins are of great concern because they are the most common food-borne mycotoxins and environmental contaminants worldwide. Fusaric acid (FA), Deoxynivalenol (DON), Zearalenone (ZEA), T-2 toxin (T-2), and Fumonisin B1 (FB1) are important Fusarium toxins contaminating feeds and food and can cause serious health problems. FA can synergize with some other Fusarium toxins to enhance overall toxicity. However, the underlying molecular mechanism remains poorly understood. In this study, our CRISPR screening revealed Malate dehydrogenase 2 (MDH2) and Pyruvate dehydrogenase E1 subunit beta (PDHB) are the key genes for FAinduced cell death. Pathways associated with mitochondrial function, notably the TCA cycle, play a significant role in FA cytotoxicity. We found that MDH2 and PDHB depletion reduced FA-induced cell death, ROS accumulation, and the expression of caspase-3 and HIF-1 alpha. The cell viability assays and flow cytometry demonstrated that MDH2 knockout but not PDHB decreased DON, ZEA, T-2, and FB1-induced cytotoxicity, apoptosis, and ROS accumulation. MDH2 inhibitor LW6 also decreased DON, ZEA, T-2, and FB1-induced toxicity. This suggested that MDH2, but not PDHB, is a common regulator of broad-spectrum Fusarium toxin (FA, DON, ZEA, T-2, and FB1)-induced cell death. Our work provides new avenues for the treatment of Fusarium toxin toxicity.

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