April 2014
Volume 55, Issue 13
ARVO Annual Meeting Abstract  |   April 2014
Mismatch Mitochondrial DNA Sequence in Diabetic Retinopathy
Author Affiliations & Notes
  • Manish Mishra
    Kresge Eye Institute, Detroit, MI
  • Renu Kowluru
    Kresge Eye Institute, Detroit, MI
  • Footnotes
    Commercial Relationships Manish Mishra, None; Renu Kowluru, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 5832. doi:
  • Views
  • Share
  • Tools
    • Alerts
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Manish Mishra, Renu Kowluru; Mismatch Mitochondrial DNA Sequence in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5832.

      Download citation file:

      © ARVO (1962-2015); The Authors (2016-present)

  • Supplements

Purpose: In diabetic retinopathy, reactive oxygen species (ROS) are elevated in the retina, mitochondrial DNA (mtDNA) is oxidatively modified, and the base excision repair (BER) machinery is compromised, raising a possibility of mismatch base pairs in the DNA. To repair the base mismatches incorporated during faulty BER, the cell is also equipped with mismatch repair (MMR) system consisting of the key regulatory proteins Mlh1 and Msh2. While Msh2 is largely associated with nuclear DNA polymerase B, Mlh1 is mainly associated with mitochondrial polymerase gamma (POLG), and we have shown that its expression in the retina is downregulated in diabetes. The aim of present study is to investigate the role of MMR system, and subsequently mtDNA sequence mismatch, in diabetic retinopathy.

Methods: Gene expressions of Mlh1 and Msh2 were quantified in the retina from streptozotocin-induced diabetic rats by q-PCR, and their protein expressions by western blot analysis. Sequence mismatch of mtDNA was examined using Surveyor nuclease assay kit for mismatch specific nuclease digestion assay. To confirm the role of Mlh1 and Msh2 in diabetic retinopathy, effect of high glucose on mtDNA mismatch and cell apoptosis was investigated in retinal endothelial cells overexpressing Mlh1 or Msh2.

Results: Diabetes decreased the expression (gene and protein) of Mlh1 and Msh2 in the retina, and increased mtDNA sequence mismatch and fragmentation. Overexpression of Mlh1 in retinal endothelial cells significantly ameliorated glucose-induced increase in mtDNA sequence mismatch and fragmentation, and also prevented increase in cell apoptosis. However, overexpression of Msh2 had partial beneficial effect on mtDNA fragmentation and cell apoptosis.

Conclusions: Better protection of mtDNA fragmentation and cell apoptosis by Mlh1 than by Msh2 suggests that impaired repair of the mismatch base pairs in the mtDNA plays significant role in the development of diabetic retinopathy. Thus, regulation of mitochondrial mismatch repair system could ameliorate mtDNA damage, and inhibit the development of this blinding disease.

Keywords: 499 diabetic retinopathy • 600 mitochondria  

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.