Epigenetic Modification of Mitochondrial DNA in the Development of Diabetic Retinopathy

摘要: In the pathogenesis of diabetic retinopathy, retinal mitochondria become dysfunctional, initiating apoptotic machinery, and capillary cell apoptosis precedes development histopathology associated with retinopathy.1–3 Mammalian are equipped their own double-stranded circular DNA (mtDNA), its two strands separated by a noncoding regulatory region, displacement loop (D-loop), which contains essential transcription replication elements.4 Due to lack supporting histones, close proximity superoxide-generating electron transport chain (ETC), mtDNA is prone oxidative damage.5,6 Our previous studies7–10 have shown that diabetes damages reduces biogenesis, damage more extensive at D-loop than other regions mtDNA. Mitochondrial encodes 37 genes, 13 these genes make proteins in ETC system for phosphorylation.11 mtDNA-encoded NADH dehydrogenase 1 6 (ND1 ND6) complex I cytochrome b (Cytb) III becomes subnormal,8,9 activity compromised, fueling into self-perpetuating cycle superoxide accumulation.8,12 Recent studies13,14 environment favors methylation CpG dinucleotides forming 5-methylcytosine (5mC). catalyzed methyltransferases (Dnmts) commonly gene silencing.15 The Dnmts themselves redox-sensitive enzymes, can enhance via deprotonating cytosine molecule accelerating reaction S-adenosyl-L-methionine.16 diabetes, Dnmt increased, enzyme, polymerase γ-1 (POLG1), hypermethylated binding impaired, resulting decreased biogenesis.10,17 Although represents <1% total cellular DNA, it has ∼440 sites, been regulate copy numbers18 chronic diseases, including amyotrophic lateral sclerosis cancer.19 Dnmt1, major enzyme responsible maintenance patterns, mitochondrial targeting sequence, colorectal cancer altered expression ND2.20 How affects remains be elucidated. The aim this study was investigate role hypermethylation retinopathy. Using endothelial cells, we investigated effect hyperglycemia on mtDNA, especially region. specific Dnmt1 regulation evaluated using Dnmt1-small interfering RNA (siRNA) transfected cells. results were confirmed microvasculature from human donors documented