Diabetes induces TRIM46-mediated ubiquitination of GPx4 in the cytosol and impairs its mitochondrial import, leading to mitochondrial damage and cell death in diabetic retinopathy.
High glucose significantly increased GPx4 ubiquitination in both retinal endothelial cells and Müller cells.
High glucose inhibited both cytosolic and mitochondrial GPx4 activity by more than 30%.
High glucose upregulated TRIM46 expression and increased TRIM46-GPx4 interactions in retinal cells.
High glucose impaired GPx4 mitochondrial import without affecting TRIM46 mitochondrial import.
TRIM46-siRNA knockdown prevented the decrease in both cytosolic and mitochondrial GPx4 activities.
Retinas from streptozotocin-induced diabetic mice showed increased TRIM46, increased ubiquitinated GPx4, and decreased GPx4 activity.
Retinas from human donors with documented diabetic retinopathy showed the same pattern of increased TRIM46, increased ubiquitinated GPx4, and decreased GPx4 activity.
This research investigates why a protective antioxidant enzyme called GPx4 stops working properly in the eyes of people with diabetes, contributing to diabetic retinopathy — a leading cause of blindness. GPx4 normally neutralizes harmful fatty acid damage in cells, particularly in the energy-producing compartments of cells called mitochondria. The study found that high blood sugar levels trigger a cellular 'tagging' process called ubiquitination, driven by a protein called TRIM46, which marks GPx4 for degradation and prevents it from getting into mitochondria where it is needed most. This causes mitochondrial damage and eventually cell death in the retina. The researchers confirmed these findings across multiple models: laboratory-grown human retinal cells exposed to high glucose, diabetic mice, and actual retinal tissue from human donors with diabetic retinopathy. In all cases, TRIM46 levels were elevated, more GPx4 was tagged for destruction, and GPx4 activity was reduced by more than 30%. Importantly, when researchers blocked TRIM46 using a genetic silencing technique, they were able to prevent the loss of GPx4 activity, suggesting that TRIM46 is a key driver of this damaging process. This research suggests that the TRIM46-GPx4 pathway could be an important target for developing new treatments to slow or prevent diabetic retinopathy. By understanding how GPx4 is regulated in diabetes, scientists may be able to design therapies that preserve its protective function in the retina, potentially reducing oxidative stress and mitochondrial damage that contribute to vision loss in diabetic patients.
Malaviya P, Kowluru R. (2026). Regulation of Glutathione Peroxidase 4 in Diabetic Retinopathy.. International journal of molecular sciences. https://doi.org/10.3390/ijms27177815