Zearalenone Regulates the Proliferation and Apoptosis of Antler Mesenchymal Cells Through Impairing Mitochondrial Function

Zearalenone (ZEA), a prevalent mycotoxin of moldy cereals, has exhibited the detrimental effects on various organs, but its influence on antler development remains unknown. Proliferation of mesenchymal cells (MSCs) is crucial for antler development. This study investigated the effects of ZEA on the proliferation and apoptosis of MSCs and explored its underlying regulatory mechanism involved in the TAZ, NRF2, GSH, ROS and mitochondrial function using flow cytometry, real-time PCR, western blotting, dual luciferase assay, various fluorescent probes, etc. Our results demonstrated that ZEA restrained the proliferation of MSCs together with the decline of cell proportion for S and G2/M phases, while facilitated the apoptosis of MSCs. Meanwhile, treatment with ZEA brought about the inhibition of TAZ and NRF2 expression followed by the attenuation of TAZ/TEAD and NRF2 transcriptional activity. Activation of TAZ and NRF2 neutralized the anti-proliferative effect of ZEA and protected the ZEA-treated MSCs against apoptosis. Moreover, TAZ acted as an intermediate to mediate the regulation of ZEA on NRF2. Further analysis revealed that ZEA induced lipid peroxidation through enhancing intracellular ROS dependent on GSH depletion with the reduced enzymic activities for GPX and GR, but these effects were rescued by the activation of NRF2. In MSCs, ZEA disrupted the mitochondrial network morphology, lessened the ATP production and promoted the mitochondrial depolarization and mitochondrial permeability transition pore opening, whereas addition of ROS scavenger alleviated above aberrant mitochondrial function. Collectively, ZEA might control the proliferation and apoptosis of antler MSCs through impairing mitochondrial function dependent on TAZ-NRF2-GSH-ROS pathway.