Measurement of Systemic Mitochondrial Function in Advanced Primary Open-Angle Glaucoma and Leber Hereditary Optic Neuropathy.

Nicole J Van Bergen,Lisa S Kearns,Jonathan G Crowston,Shiwani Sharma,Kathryn P Burdon,Jamie E Craig,Ian A Trounce,David A Mackey,Alex W Hewitt,Demetrios Vavvas

doi:10.1371/journal.pone.0140919

Abstract

Primary Open Angle Glaucoma (POAG) is a common neurodegenerative disease characterized by the selective and gradual loss of retinal ganglion cells (RGCs). Aging and increased intraocular pressure (IOP) are glaucoma risk factors; nevertheless patients deteriorate at all levels of IOP, implying other causative factors. Recent evidence presents mitochondrial oxidative phosphorylation (OXPHOS) complex-I impairments in POAG. Leber Hereditary Optic Neuropathy (LHON) patients suffer specific and rapid loss of RGCs, predominantly in young adult males, due to complex-I mutations in the mitochondrial genome. This study directly compares the degree of OXPHOS impairment in POAG and LHON patients, testing the hypothesis that the milder clinical disease in POAG is due to a milder complex-I impairment. To assess overall mitochondrial capacity, cells can be forced to produce ATP primarily from mitochondrial OXPHOS by switching the media carbon source to galactose. Under these conditions POAG lymphoblasts grew 1.47 times slower than controls, whilst LHON lymphoblasts demonstrated a greater degree of growth impairment (2.35 times slower). Complex-I enzyme specific activity was reduced by 18% in POAG lymphoblasts and by 29% in LHON lymphoblasts. We also assessed complex-I ATP synthesis, which was 19% decreased in POAG patients and 17% decreased in LHON patients. This study demonstrates both POAG and LHON lymphoblasts have impaired complex-I, and in the majority of aspects the functional defects in POAG were milder than LHON, which could reflect the milder disease development of POAG. This new evidence places POAG in the spectrum of mitochondrial optic neuropathies and raises the possibility for new therapeutic targets aimed at improving mitochondrial function.

Highlights

Glaucoma is a neurodegenerative disease characterized by the selective and accelerated loss of retinal ganglion cells (RGCs)
Impaired population doubling time was observed in both Primary Open-Angle Glaucoma (POAG) and Leber Hereditary Optic Neuropathy (LHON) lymphoblasts when they were forced to grow in galactose media
The impairment in lymphoblast population doubling time was greater in LHON lymphoblasts compared to POAG lymphoblasts

Summary

Introduction

Glaucoma is a neurodegenerative disease characterized by the selective and accelerated loss of retinal ganglion cells (RGCs). In late-stage disease POAG and LHON share phenotypical similarities at the optic nerve head, and both suffer RGC loss [14,15,16]. A high density of mitochondria at the optic nerve head suggests a particular dependence on mitochondrial function in this location, which predisposes RGCs to metabolic failure when additional stresses such as age and increased intraocular pressure (IOP) occur [17]. Functional studies from advanced POAG patients revealed a decreased total mitochondrial respiratory function in lymphocytes [22] and trabecular meshwork cells [23] that was likely due to a complex-I impairment [24]. We compare the degree of complex-I impairment in advanced POAG patients to that of LHON patients with advanced vision loss to correlate the degree of mitochondrial impairment to that of disease development

Methods

Results

Conclusion