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Epigenetic modifications, such as mtDNA hypermethylation, impair mitochondrial gene expression and respiration, while decreased SIRT3 activity contributes to the loss of redox homeostasis in retinal endothelial cells ( Figure 2 illustrates recent findings regarding mitochondrial structural and functional dysregulation under hyperglycemic stress, including fission/fusion imbalance, impaired mitophagy, and persistent ROS amplification