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

Myoung Sup Shim,Beatrice Y J T Yue,Guy A Perkins,Won-Kyu Ju,Masaru Inatani,Yuji Takihara,Robert N Weinreb,Keun-Young Kim,Takeshi Iwata

doi:10.1038/srep33830

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−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.

Highlights

(OPA1) and mitofusins are required for mitochondria fusion, dynamin-related protein-1 (DRP1) regulates mitochondrial fission[20,21,22]
Using aged (16-month-old) E50K-mutation-carrying transgenic (E50K−tg) mice, we found that the E50K expression significantly increased Bax protein expression by 4.28 ± 0.46-fold in their retina compared with age-matched wild-type (WT) control mice (Fig. 1a)
We noted that the E50K mutation significantly increased the protein expression levels of mitochondrial OXPHOS complex I (Cx I) by 2.64 ± 0.63-fold in the retina of E50K−tg mice compared with WT mice, respectively (Fig. 1b)

Summary

Introduction

(OPA1) and mitofusins are required for mitochondria fusion, dynamin-related protein-1 (DRP1) regulates mitochondrial fission[20,21,22]. More recent data further indicated that either OPA1 overexpression or DRP1 inhibition can enhance RGC survival and rescue its axon by preserving mitochondrial integrity in glaucomatous DBA/2J mice[19,23]. These findings strongly suggest the presence of a distinct mitochondrial dynamics-associated degenerative pathway in glaucomatous neurodegeneration. We report here for the first time that E50K mutation modifies the Bax pathway and alters mitochondrial dynamics, as well as triggers mitochondrial degradation and autophagosome and/or mitophagosome formation in aged E50K-mutation-carrying transgenic (E50K−tg) mice in vivo and primary RGCs in vitro

Methods

Results

Conclusion