title: Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration.
abstract: 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-tgmice 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.
authors.affiliation: Hamilton Glaucoma Center, Department of Ophthalmology, and Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA.
authors.forename: Myoung Sup
authors.initials: MS
authors.lastname: Shim
authors.affiliation: Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takihara
authors.affiliation: Center for Research in Biological Systems, National Center for Microscopy and Imaging Research and Department of Neuroscience, University of California San Diego, La Jolla, CA, USA.
authors.forename: Keun-Young
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwata
authors.affiliation: Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, IL USA.
authors.forename: Beatrice Y J T
authors.initials: BY
authors.lastname: Yue
authors.affiliation: Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Inatani
authors.affiliation: Hamilton Glaucoma Center, Department of Ophthalmology, and Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Weinreb
authors.affiliation: Center for Research in Biological Systems, National Center for Microscopy and Imaging Research and Department of Neuroscience, University of California San Diego, La Jolla, CA, USA.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Perkins
authors.affiliation: Hamilton Glaucoma Center, Department of Ophthalmology, and Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA.
authors.forename: Won-Kyu
authors.initials: WK
authors.lastname: Ju