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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. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
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.
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).
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.
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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