1. Academic Validation
  2. Zearalenone Induces MLKL-Dependent Necroptosis in Goat Endometrial Stromal Cells via the Calcium Overload/ROS Pathway

Zearalenone Induces MLKL-Dependent Necroptosis in Goat Endometrial Stromal Cells via the Calcium Overload/ROS Pathway

  • Int J Mol Sci. 2022 Sep 5;23(17):10170. doi: 10.3390/ijms231710170.
Yanyan Yi 1 2 Kangkang Gao 1 2 Liang Zhang 1 Pengfei Lin 1 2 Aihua Wang 1 2 Yaping Jin 1 2
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Northwest A&F University, Xianyang 712100, China.
  • 2 Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Xianyang 712100, China.
Abstract

Zearalenone (ZEA) is a Fungal mycotoxin known to exert strong reproductive toxicity in Animals. As a newly identified type of programmed cell death, Necroptosis is regulated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed-lineage kinase domain-like pseudokinase (MLKL). However, the role and mechanism of Necroptosis in ZEA toxicity remain unclear. In this study, we confirmed the involvement of Necroptosis in ZEA-induced cell death in goat endometrial stromal cells (gESCs). The release of Lactate Dehydrogenase (LDH) and the production of PI-positive cells markedly increased. At the same time, the expression of RIPK1 and RIPK3 mRNAs and P-RIPK3 and P-MLKL proteins were significantly upregulated in ZEA-treated gESCs. Importantly, the MLKL inhibitor necrosulfonamide (NSA) dramatically attenuated gESCs Necroptosis and powerfully blocked ZEA-induced Reactive Oxygen Species (ROS) generation and mitochondrial dysfunction. The Reactive Oxygen Species (ROS) scavengers and N-acetylcysteine (NAC) inhibited ZEA-induced cell death. In addition, the inhibition of MLKL alleviated the intracellular CA2+ overload caused by ZEA. The calcium chelator BAPTA-AM markedly suppressed ROS production and mitochondrial damage, thus inhibiting ZEA-induced Necroptosis. Therefore, our results revealed the mechanism by which ZEA triggers gESCs Necroptosis, which may provide a new therapeutic strategy for ZEA poisoning.

Keywords

Ca2+ overload; goat endometrial stromal cells (gESCs); mitochondria damage; necroptosis; reactive oxygen species (ROS); zearalenone (ZEA).

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