Mitochondrial Dysfunction Triggered by T-2 Toxin-Induced Thioredoxin Reductase 2 (TXNRD2) Depletion and Its Molecular Mechanism

Abstract

The T-2 toxin is a prevalent trichothecene mycotoxin that threatens food safety and animal health, yet its direct mitochondrial targets remain poorly defined. Using network toxicology and in vitro validation in porcine renal PK15 cells, thioredoxin reductase 2 (TXNRD2) was identified as the most significantly downregulated mitochondrial selenoprotein upon T-2 toxin exposure. Molecular docking and enzymatic assays demonstrated that T-2 binds to and inhibits TXNRD2 by occupying its FAD/NADPH-binding pocket. Notably, SeMet restored TXNRD2 expression and partially rescued mitochondrial injury, whereas direct TXNRD2 overexpression independently conferred comparable protection, confirming TXNRD2 as the key downstream effector. These interventions attenuated the abnormal elevation of intracellular ATP content and reduced ROS overproduction by approximately 39%. Conversely, TXNRD2 knockdown attenuated SeMet’s efficacy to establish TXNRD2 as a direct mitochondrial target of the T-2 toxin. Supplementation with SeMet protected cells by restoring both the expression and enzymatic activity of TXNRD2 and preventing T-2 toxin-induced cytotoxicity.