Diabetic Retinopathy and Regulation of Mitochondrial Glutathione-Glutathione Peroxidase Axis in Hyperhomocysteinemia

• Main Authors: Pooja Malaviya (Author), Renu A. Kowluru (Author)
• Format: Book
• Published: MDPI AG, 2024-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antiox13030254; 2076-3921
• Keywords: diabetic retinopathy; DNA methylation; glutathione; peroxidase; homocysteine; mitochondria; Therapeutics. Pharmacology; RM1-950
• Source: Antioxidants, Vol 13, Iss 3, p 254 (2024)

Diabetic patients have elevated homocysteine levels, and hyperhomocysteinemia is shown to exacerbate mitochondrial damage, which plays a central role in diabetic retinopathy. Glutathione peroxidases (GPx) catalyze hydrogen peroxide (H₂O₂) reduction using glutathione (GSH) as a cofactor. GSH and GPx are mainly cytosolic but are also present in the mitochondria to neutralize H₂O₂ produced by superoxide dismutase, and in diabetes, they are downregulated. Hyperhomocysteinemia also disrupts the balance between S-adenosyl-L-homocysteine and S-adenosylmethionine (SAM); SAM is also a methyl donor for DNA methylation. The aim of this study was to investigate the role of homocysteine in mitochondrial GSH-GPx1 regulation in diabetic retinopathy. Human retinal endothelial cells in 20 mM D-glucose + high homocysteine were analyzed for ROS, GSH and GPx in the mitochondria, and SAM levels and <i>GPx1</i> promoter DNA methylation were also studied (5-methylcytosine and MS-PCR). The results were confirmed in the retina from streptozotocin-induced hyperhomocysteinemic (cystathionine-β-synthase-deficient) diabetic mice. High homocysteine exacerbated the glucose-induced decrease in GSH levels and GPx activity in the mitochondria and the downregulation of <i>GPx1</i> transcripts and further increased SAM levels and <i>GPx1</i> promoter DNA methylation. Similar results were obtained in a hyperglycemic-hyperhomocysteinemic mouse model. Thus, elevated homocysteine in diabetes hypermethylates <i>GPx1</i> promoter, thus decreasing the mitochondrial GPx/GSH pool and exacerbating mitochondrial damage. Modulating hyperhomocysteinemia could be a potential therapeutic avenue to target mitochondrial dysfunction in diabetic retinopathy.