Diabetic Retinopathy and Regulation of Mitochondrial Glutathione-Glutathione Peroxidase Axis in Hyperhomocysteinemia
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 (H<sub>2</sub>O<sub>2</sub>) reduction using...
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| Main Authors: | , |
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| Format: | Book |
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MDPI AG,
2024-02-01T00:00:00Z.
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| Summary: | 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 (H<sub>2</sub>O<sub>2</sub>) reduction using glutathione (GSH) as a cofactor. GSH and GPx are mainly cytosolic but are also present in the mitochondria to neutralize H<sub>2</sub>O<sub>2</sub> 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. |
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| Item Description: | 10.3390/antiox13030254 2076-3921 |