Mishra 2014 Invest Ophthalmol Vis Sci

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Mishra M, Kowluru RA (2014) Retinal mitochondrial DNA mismatch repair in the development of diabetic retinopathy, and its continued progression after termination of hyperglycemia. Invest Ophthalmol Vis Sci. 55:6960-7.

» PMID: 25249609 PDF

Mishra M, Kowluru RA (2014) Invest Ophthalmol Vis Sci

Abstract: Mitochondrial DNA (mtDNA) is damaged in the retina in diabetes, and mitochondria copy numbers are decreased. The displacement-loop (D-loop) of the mtDNA, the region with transcription/ replication elements, experiences more damage than other regions of mtDNA. Our aim is to examine the role of DNA mismatch repair (MMR) in mitochondria homeostasis in diabetic retinopathy, and in its continued progression after cessation of hyperglycemia.

Effect of hyperglycemia on sequence variants in the D-loop region was investigated in retinal endothelial cells and in the retina from streptozotocin-induced diabetic rat using mismatchspecific Surveyor nuclease. Role of MMR machinery in mtDNA damage and mitochondrial respiration was investigated in retinal endothelial cells overexpressing Mlh1, a MMR enzyme mainly associated with mtDNA polymerase gamma, or Msh2 (associated with nuclear polymerase beta).

Hyperglycemia increased sequence variants in the D-loop region. While overexpression of Mlh1in endothelial cells ameliorated glucose-induced increase in Dloop sequence variants, decrease in respiration rate and increase in apoptosis, overexpression of Msh2 did not protect the mitochondria damage. Termination of hyperglycemia failed to reverse decrease in MMR enzymes and increase in D-loop sequence variants.

Due to compromised MMR system, the sequence variants in the D-loop region are not repaired, and this results in impaired mtDNA transcription. Mitochondria become dysfunctional, and they continue to be dysfunctional even after hyperglycemia is terminated, contributing to the development, and progression of diabetic retinopathy. Strategies targeting mitochondrial MMR machinery could help maintain mitochondria homeostasis, and inhibit the development of diabetic retinopathy and its continued progression.

Keywords: Diabetic retinopathy, DNA repair, Mitochondria damage, mtDNA mismatch, Metabolic memory

Labels: MiParea: Respiration, mtDNA;mt-genetics, Genetic knockout;overexpression, Patients  Pathology: Diabetes  Stress:Cell death  Organism: Bovines  Tissue;cell: Endothelial;epithelial;mesothelial cell  Preparation: Intact cells 

Coupling state: ROUTINE 

HRR: Oxygraph-2k