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

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

  • J Hazard Mater. 2024 Sep 23:480:135937. doi: 10.1016/j.jhazmat.2024.135937.
Wei-Tao Shi 1,  Chun-Peng Yao 2,  Wen-Hua Liu 3,  Wan-Yi Cao 3,  Wei Shao 4,  Shen-Quan Liao 5,  Ting Yu 3,  Qing-Feng Zhu 3,  Zhuang Chen 3,  Ying-Jie Zang 3,  Muhammad Farooq 3,  Wen-Kang Wei 6,  Xiao-Ai Zhang 7
Affiliations

Affiliations

  • 1 Agro-biological Gene Research Center of Guangdong Academy of Agricultural Sciences, State Key Laboratory of Swine and Poultry Breeding Industry, Guangzhou 510640, PR China; Xinjiang Agricultural University, College of Animal Science, Urumqi 830052, PR China.
  • 2 Vegetable Research Institute of Guangdong Academy of Agricultural Sciences, Guangdong Key Laboratory for New Technology Research of Vegetables, Guangzhou 510640, PR China.
  • 3 Agro-biological Gene Research Center of Guangdong Academy of Agricultural Sciences, State Key Laboratory of Swine and Poultry Breeding Industry, Guangzhou 510640, PR China.
  • 4 Xinjiang Agricultural University, College of Animal Science, Urumqi 830052, PR China.
  • 5 Institute of Animal Health, Guangdong Academy of Agricultural Sciences, 510640, PR China.
  • 6 Agro-biological Gene Research Center of Guangdong Academy of Agricultural Sciences, State Key Laboratory of Swine and Poultry Breeding Industry, Guangzhou 510640, PR China. Electronic address: weiwenkang@gdaas.cn.
  • 7 Agro-biological Gene Research Center of Guangdong Academy of Agricultural Sciences, State Key Laboratory of Swine and Poultry Breeding Industry, Guangzhou 510640, PR China. Electronic address: zhangxiaoai@gdaas.cn.
PMID: 39342847 DOI: 10.1016/j.jhazmat.2024.135937
Abstract

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 FA-induced 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-1α. 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.

Keywords

CRISPR screening; Cell death; Fusaric acid; Fusarium toxin; MDH2.

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