{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Malaviya P"],"funding":["NIH HHS"],"pagination":["254"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10967481"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["13(3)"],"pubmed_abstract":["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."],"journal":["Antioxidants (Basel, Switzerland)"],"pubmed_title":["Diabetic Retinopathy and Regulation of Mitochondrial Glutathione-Glutathione Peroxidase Axis in Hyperhomocysteinemia."],"pmcid":["PMC10967481"],"funding_grant_id":["EY014370, EY017313 and EY022230"],"pubmed_authors":["Kowluru RA","Malaviya P"],"additional_accession":[]},"is_claimable":false,"name":"Diabetic Retinopathy and Regulation of Mitochondrial Glutathione-Glutathione Peroxidase Axis in Hyperhomocysteinemia.","description":"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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Feb","modification":"2025-04-21T21:30:34.827Z","creation":"2025-04-05T18:21:26.247Z"},"accession":"S-EPMC10967481","cross_references":{"pubmed":["38539790"],"doi":["10.3390/antiox13030254"]}}