title: Mitochondria DNA replication and DNA methylation in the metabolic memory associated with continued progression of diabetic retinopathy.
abstract: OBJECTIVE
  Diabetic retinopathy fails to halt after cessation of hyperglycemic insult, and a vicious cycle of mitochondria damage continues. The aim of our study was to investigate the effect of termination of hyperglycemia on retinal mtDNA replication, and elucidate the mechanism responsible for the continued mtDNA damage.
  
  
  METHODS
  Polymerase gamma 1 (POLG1), the catalytic subunit of the mitochondrial DNA replication enzyme, and the damage to the displacement loop region of mtDNA (D-loop) were analyzed in the retina from streptozotocin-diabetic rats maintained in poor glycemic control (PC, glycated hemoglobin ∼11%) or in good glycemic control (GC, glycated hemoglobin ∼6%) for 6 months, or in PC for three months followed by GC for three months (Rev). To understand the mechanism DNA methylation status of POLG1 promoter was investigated by methylation-specific PCR. The key parameters were confirmed in the isolated retinal endothelial cells exposed to high glucose, followed by normal glucose.
  
  
  RESULTS
  POLG1 continued to be down-regulated, the D-loop region damaged, and the CpG islands at the regulatory region of POLG hyper-methylated even after three months of GC that had followed three months of PC (Rev group). Similar results were observed in the retinal endothelial cells exposed to normal glucose after being exposed to high glucose.
  
  
  CONCLUSIONS
  Continued hypermethylation of the CpG sites at the regulatory region of POLG affects its binding to the mtDNA, compromising the transcriptional activity. Modulation of DNA methylation using pharmaceutic or molecular means could help maintain mitochondria homeostasis, and prevent further progression of diabetic retinopathy.
authors: Kresge Eye Institute, Wayne State University, Detroit, Michigan, USA.
authors: Shikha
authors: S
authors: Tewari
authors: Qing
authors: Q
authors: Zhong
authors: Julia M
authors: JM
authors: Santos
authors: Renu A
authors: RA
authors: Kowluru
mesh_terms: D000818:Animals; D019175:DNA Methylation; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000201:enzymology* / Q000235:genetics; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology; D006943:Hyperglycemia / Q000201:enzymology*; D008297:Male; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000201:enzymology*
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse