June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Optineurin E50K mutation triggers oxidative stress and mitochondrial alteration in mouse retinal neurodegeneration
Author Affiliations & Notes
  • Myoung Sup Sim
    Hamilton Glaucoma Center and Department of Ophthalmology, University of California, San Diego, La Jolla, CA
  • Guy A. Perkins
    Center for Research on Biological Systems, National Center for Microscopy and Imaging Research and Department of Neuroscience, University of California San Diego, La Jolla, CA
  • Keun-Young Kim
    Center for Research on Biological Systems, National Center for Microscopy and Imaging Research and Department of Neuroscience, University of California San Diego, La Jolla, CA
  • Takeshi Iwata
    Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
  • Beatrice Yue
    Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois, Chicago, IL
  • Mark H. Ellisman
    Center for Research on Biological Systems, National Center for Microscopy and Imaging Research and Department of Neuroscience, University of California San Diego, La Jolla, CA
  • Robert N Weinreb
    Hamilton Glaucoma Center and Department of Ophthalmology, University of California, San Diego, La Jolla, CA
  • Won-Kyu Ju
    Hamilton Glaucoma Center and Department of Ophthalmology, University of California, San Diego, La Jolla, CA
  • Footnotes
    Commercial Relationships Myoung Sup Sim, None; Guy Perkins, None; Keun-Young Kim, None; Takeshi Iwata, None; Beatrice Yue, None; Mark Ellisman, None; Robert Weinreb, None; Won-Kyu Ju, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 1986. doi:
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      Myoung Sup Sim, Guy A. Perkins, Keun-Young Kim, Takeshi Iwata, Beatrice Yue, Mark H. Ellisman, Robert N Weinreb, Won-Kyu Ju; Optineurin E50K mutation triggers oxidative stress and mitochondrial alteration in mouse retinal neurodegeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1986.

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

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Abstract

Purpose: E50K mutation is the most prevalent mutation of optineurin (OPTN) that is associated with the normal tension glaucoma. Mitochondrial dysfunction has been considered as an important pathophysiological mechanism in glaucomatous neurodegeneration. The goal of this study is to determine whether OPTN E50K mutation triggers oxidative stress and mitochondrial alteration in mouse retinal neurodegeneration.

Methods: Sixteen-month-old E50K mutation-carrying transgenic (E50K-tg) mice were used. Mitochondrial alterations were assessed by Western blot using antibodies raised against superoxide dismutase 2 (SOD2), oxidative phosphorylation (OXPHOS) complex, peroxisome-proliferator-activated receptor-g-coactivator-1 alpha (PGC-1α) and mitochondrial transcription factor A (Tfam). Mitochondrial morphology and ultrastructural change were analyzed by transmission electron microscopy (EM). Mitophagosome formation was assessed by Western blot and immunohistochemisty using antibody raised against LC3 and by EM tomography. Apoptotic pathway was assessed by Western blot using antibodies raised against Bax and phosphorylated Bad (pBad).

Results: Oxidative stress and mitochondrial alteration were induced in the retinas of E50K-tg mice, as evidenced by increasing SOD2, OXPHOS complex I and II, PGC-1α and Tfam protein expression. EM analysis exhibited not only mitochondrial fission by increasing mitochondrial number and decreasing mitochondrial length but also mitochondrial loss by decreasing mitochondrial volume density in the axons of the glial lamina in E50K-tg mice. A significant increase of LC3-II protein expression was observed in RGC somas and their axons in the nerve fiber layer of E50K-tg mice. In addition, mitophagosome formation was induced in the axons of the glial lamina in E50K-tg mice. Bax and pBad protein expression were significantly increased in the retinas of E50K-tg mice.

Conclusions: These results provide evidence that OPTN E50K mutation may contribute to oxidative stress-associated mitochondrial alteration and mitophagosome formation, and leads to retinal neurodegeneration by modulating Bax/Bad-mediated apoptotic pathway in transgenic mice.

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