March 2012
Volume 53, Issue 14
ARVO Annual Meeting Abstract  |   March 2012
Image Registration Reveals Sites of Injury from Mitochondrial Oxidative Stress in the Retinal Pigment Epithelium
Author Affiliations & Notes
  • Alfred S. Lewin
    Molecular Genetics & Microbio,
    University of Florida, Gainesville, Florida
  • Mark P. Krebs
    The Jackson Laboratory, Bar Harbor, Maine
  • Soo Jung Soo
    Molecular Genetics & Microbio,
    University of Florida, Gainesville, Florida
  • Kyle Jones
    Molecular Genetics & Microbio,
    University of Florida, Gainesville, Florida
  • Haoyu Mao
    Molecular Genetics & Microbiology,
    University of Florida, Gainesville, Florida
  • William W. Hauswirth
    Dept of Ophthalmology, Univ of Florida Coll of Medicine, Gainesville, Florida
  • Footnotes
    Commercial Relationships  Alfred S. Lewin, Alcon (C); Mark P. Krebs, None; Soo Jung Soo, None; Kyle Jones, None; Haoyu Mao, None; William W. Hauswirth, AGTC (P)
  • Footnotes
    Support  NIH Grant EY02025; James and Esther King Biomedical Research Program grant 10KG-08; macular Research Foundation
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 6509. doi:
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      Alfred S. Lewin, Mark P. Krebs, Soo Jung Soo, Kyle Jones, Haoyu Mao, William W. Hauswirth; Image Registration Reveals Sites of Injury from Mitochondrial Oxidative Stress in the Retinal Pigment Epithelium. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6509.

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

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To test the hypothesis that mitochondrial oxidative stress in the retinal pigment epithelium (RPE) of the mouse contributes to retinal pathology similar to that observed in atrophic age related macular degeneration (AMD).


To increase mitochondrial oxidative stress in the RPE of mice, the gene (Sod2) for manganese superoxide dismutase (MnSOD) was deleted using the Cre-lox system in which Cre recombinase was expressed only in the RPE following induction with doxycycline. Immunohistochemistry was used to confirm RPE specific reduction in MnSOD, increase in oxidative stress and up-regulation of complement related proteins. Digitial fundus imaging was used to identify pigmentary and vascular abnormalities in the retina. Spectral domain optical coherence tomography (SD-OCT) was used to document changes in the photoreceptor layer and RPE in living mice. Light and electron microscopy were used to assess RPE pathology.


Deletion of Sod2 in the RPE led to evidence of oxidative stress, including increased 4-hydroxy-2-noneal modified proteins and 2-OH-guanosine modified DNA. Pigmentary abnormalities were detected within two months of induction of Cre and, using the retinal vasculature as landmarks, these were correlated with sub-retinal or sub-RPE hyperreflective lesions in SD-OCT. SD-OCT also revealed thinning of the outer nuclear layer, suggesting death of photoreceptor cells. Deposition of complement regulatory protein CD46 in the RPE was associated with areas of retinal injury. Deposits along the basement membrane of the RPE were detected by electron microscopy, which also revealed severely damaged mitochondrial in the following deletion of Sod2. There was no evidence of choroidal neovascularization in this model, at least within the first year of observation.


Imaging methods, including SD-OCT and fundus imaging as used in the clinical diagnosis of AMD revealed morphological abnormalities in this mouse model that are analogous to some of the findings in patients with geographic atrophy. These findings were confirmed and extended by histology and electron microscopy. This mouse model may therefore be useful for testing treatments to halt the progression of atrophic AMD.

Keywords: retinal pigment epithelium • oxidation/oxidative or free radical damage • mitochondria 

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