A compensatory mechanism protects retinal mitochondria from initial insult in diabetic retinopathy

Free Radic Biol Med. 2012 Nov 1;53(9):1729-37. doi: 10.1016/j.freeradbiomed.2012.08.588. Epub 2012 Sep 1.


In the pathogenesis of diabetic retinopathy, an increase in retinal oxidative stress precedes mitochondrial dysfunction and capillary cell apoptosis. This study is designed to understand the mechanism responsible for the protection of mitochondria damage in the early stages of diabetic retinopathy. After 15 days-12 months of streptozotocin-induced diabetes in rats, retina was analyzed for mitochondria DNA (mtDNA) damage by extended length PCR. DNA repair enzyme and replication machinery were quantified in the mitochondria, and the binding of mitochondrial transcriptional factor A (TFAM) with mtDNA was analyzed by ChIP. Key parameters were confirmed in the retinal endothelial cells incubated in 20mM glucose for 6-96h. Although reactive oxygen species (ROS) were increased within 15 days of diabetes, mtDNA damage was observed at 6 months of diabetes. After 15 days of diabetes DNA repair/replication enzymes were significantly increased in the mitochondria, but at 2 months, their mitochondrial accumulation started to come down, and mtDNA copy number and binding of TFAM with mtDNA became significantly elevated. However, at 6 months of diabetes, the repair/replication machinery became subnormal and mtDNA copy number significantly decreased. A similar temporal relationship was observed in endothelial cells exposed to high glucose. Thus, in the early stages of diabetes, increased mtDNA biogenesis and repair compensates for the ROS-induced damage, but, with sustained insult, this mechanism is overwhelmed, and mtDNA and electron transport chain (ETC) are damaged. The compromised ETC propagates a vicious cycle of ROS and the dysfunctional mitochondria fuels loss of capillary cells by initiating their apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cattle
  • Cells, Cultured
  • Cytochromes b / genetics
  • Cytochromes b / metabolism
  • DNA Damage
  • DNA Glycosylases / genetics
  • DNA Glycosylases / metabolism
  • DNA, Mitochondrial
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetic Retinopathy / etiology
  • Diabetic Retinopathy / metabolism*
  • Diabetic Retinopathy / pathology
  • Electron Transport
  • Endothelial Cells / metabolism
  • Gene Dosage
  • Gene Expression
  • Glucose / pharmacology
  • Glucose / physiology
  • Male
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Oxidative Stress
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism
  • Retina / metabolism*
  • Retina / pathology
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • DNA, Mitochondrial
  • Reactive Oxygen Species
  • Tfam protein, rat
  • Transcription Factors
  • Cytochromes b
  • Superoxide Dismutase
  • superoxide dismutase 2
  • DNA-Directed DNA Polymerase
  • DNA Glycosylases
  • OGG1 protein, rat
  • Glucose