Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration

Mutations in optineurin (OPTN) are linked to the pathology of primary open angle glaucoma (POAG) and amyotrophic lateral sclerosis. Emerging evidence indicates that OPTN mutation is involved in accumulation of damaged mitochondria and defective mitophagy. Nevertheless, the role played by an OPTN E50...

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Autores principales: Shim, Myoung Sup, Takihara, Yuji, Kim, Keun-Young, Iwata, Takeshi, Yue, Beatrice Y. J. T., Inatani, Masaru, Weinreb, Robert N., Perkins, Guy A., Ju, Won-Kyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031982/
https://www.ncbi.nlm.nih.gov/pubmed/27654856
http://dx.doi.org/10.1038/srep33830
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author Shim, Myoung Sup
Takihara, Yuji
Kim, Keun-Young
Iwata, Takeshi
Yue, Beatrice Y. J. T.
Inatani, Masaru
Weinreb, Robert N.
Perkins, Guy A.
Ju, Won-Kyu
author_facet Shim, Myoung Sup
Takihara, Yuji
Kim, Keun-Young
Iwata, Takeshi
Yue, Beatrice Y. J. T.
Inatani, Masaru
Weinreb, Robert N.
Perkins, Guy A.
Ju, Won-Kyu
author_sort Shim, Myoung Sup
collection PubMed
description Mutations in optineurin (OPTN) are linked to the pathology of primary open angle glaucoma (POAG) and amyotrophic lateral sclerosis. Emerging evidence indicates that OPTN mutation is involved in accumulation of damaged mitochondria and defective mitophagy. Nevertheless, the role played by an OPTN E50K mutation in the pathogenic mitochondrial mechanism that underlies retinal ganglion cell (RGC) degeneration in POAG remains unknown. We show here that E50K expression induces mitochondrial fission-mediated mitochondrial degradation and mitophagy in the axons of the glial lamina of aged E50K(−tg) mice in vivo. While E50K activates the Bax pathway and oxidative stress, and triggers dynamics alteration-mediated mitochondrial degradation and mitophagy in RGC somas in vitro, it does not affect transport dynamics and fission of mitochondria in RGC axons in vitro. These results strongly suggest that E50K is associated with mitochondrial dysfunction in RGC degeneration in synergy with environmental factors such as aging and/or oxidative stress.
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spelling pubmed-50319822016-09-29 Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration Shim, Myoung Sup Takihara, Yuji Kim, Keun-Young Iwata, Takeshi Yue, Beatrice Y. J. T. Inatani, Masaru Weinreb, Robert N. Perkins, Guy A. Ju, Won-Kyu Sci Rep Article Mutations in optineurin (OPTN) are linked to the pathology of primary open angle glaucoma (POAG) and amyotrophic lateral sclerosis. Emerging evidence indicates that OPTN mutation is involved in accumulation of damaged mitochondria and defective mitophagy. Nevertheless, the role played by an OPTN E50K mutation in the pathogenic mitochondrial mechanism that underlies retinal ganglion cell (RGC) degeneration in POAG remains unknown. We show here that E50K expression induces mitochondrial fission-mediated mitochondrial degradation and mitophagy in the axons of the glial lamina of aged E50K(−tg) mice in vivo. While E50K activates the Bax pathway and oxidative stress, and triggers dynamics alteration-mediated mitochondrial degradation and mitophagy in RGC somas in vitro, it does not affect transport dynamics and fission of mitochondria in RGC axons in vitro. These results strongly suggest that E50K is associated with mitochondrial dysfunction in RGC degeneration in synergy with environmental factors such as aging and/or oxidative stress. Nature Publishing Group 2016-09-22 /pmc/articles/PMC5031982/ /pubmed/27654856 http://dx.doi.org/10.1038/srep33830 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Shim, Myoung Sup
Takihara, Yuji
Kim, Keun-Young
Iwata, Takeshi
Yue, Beatrice Y. J. T.
Inatani, Masaru
Weinreb, Robert N.
Perkins, Guy A.
Ju, Won-Kyu
Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration
title Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration
title_full Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration
title_fullStr Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration
title_full_unstemmed Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration
title_short Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration
title_sort mitochondrial pathogenic mechanism and degradation in optineurin e50k mutation-mediated retinal ganglion cell degeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031982/
https://www.ncbi.nlm.nih.gov/pubmed/27654856
http://dx.doi.org/10.1038/srep33830
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