Ochratoxin A-induced mitochondrial pathway apoptosis and ferroptosis by promoting glycolysis.

Abstract

Ochratoxin A (OTA), a toxic secondary metabolite recognized for its harmful effects on the kidneys, and it is commonly present in various foods and animal feeds. Although there have been few reports on the involvement of metabolic enzymes in OTA-induced nephrotoxicity and metabolic reprogramming in OTA-induced digestive tract toxicity, it remains unclear whether OTA's primary nephrotoxic effects are mediated through metabolic reprogramming. In this study, we examined the effects of OTA and/or 2-deoxy-D-glucose (2-DG) on cell viability, levels of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and lactic acid (LA), as well as protein levels in human proximal tubule epithelial (HK-2) cells. The results indicate that OTA leads to a reduction in GSH levels and the protein levels of Lon protease 1 (Lonp1), tumor necrosis factor receptor-associated protein 1 (TRAP1), mitochondrial pyruvate carrier 1 (MPC1), glutathione peroxidase 4 (GPX4), B-cell lymphoma-2 (Bcl-2), and Bcl-2-like protein 1 (Bcl-xl), while increasing ROS, MDA, and LA levels, as well as the protein levels of glucose transporter type 1 (GLUT1), hexokinase 2 (HK2), pyruvate kinase 2 (PKM2), ATP-dependent 6-phosphofructokinase, platelet type (PFKP), long-chain fatty acid-CoA ligase 4 (ACSL4), Bcl-2-associated X protein (Bax), and cyclophilin D (CYPD) (P < 0.05). In conclusion, OTA induces mitochondrial pathway apoptosis and ferroptosis by disturbing mitochondrial homeostasis via the inhibition of Lonp1 and TRAP1, thereby reducing GSH levels, increasing ROS, MDA, and LA levels, and promoting glycolysis in vitro. This is the first report on OTA-induced mitochondrial pathway apoptosis and ferroptosis facilitated by mitochondrial homeostasis imbalance-mediated glycolysis in HK-2 cells.