Mitochondrial dysfunction and oxidative stress in corneal disease☆
Introduction
The eye is a highly specialized organ of photoreception, an optical system able to focus the light energy from the environment on to the retina, which is the receptor of the visual pathway. The cornea, the anterior transparent window of the eye, is a crucial part of this optical system, creating 80% of the refractive power of the eye. The cornea is a dome-shaped transparent structure, and its shape and clarity, are the main characteristics enabling such great refractive power. The cornea, being avascular, obtains its nutrients from the tear film, the aqueous humour and blood vessels at the peripheral edge of the cornea. Human corneal transparency is the result of a number of related factors: avascularity, structural regularity of the covering epithelium, regular arrangement of the extracellular and cellular components in the stroma and functionality of the endothelium to regulate corneal hydration (Nita and Grzybowski, 2016, Zierhut et al., 2008). The normal corneal structure comprises of five well-defined layers from the external to internal corneal surface: the epithelium (multilayer), Bowman's layer, stroma (interlaced with keratocytes), the Descemet membrane and the endothelium (monolayer) (Fig. 1). Even small malfunctions or malformations in any of these components and/or an impaired communication between them can compromise their function. The unique physiology of the cornea predisposes this structure to oxidative damage, and there is interplay between inherited and acquired mitochondrial dysfunction, oxidative damage and a number of corneal diseases.
Mitochondrial mutations and dysfunction has been implicated in other ocular conditions. The most common mitochondrial disease is Leber's hereditary optic neuropathy (LHON) (Chinnery et al., 2001). This results in the degeneration of retinal ganglion cells and a progressive degeneration of the optic nerve (Jankauskaitė et al., 2016). About 70% of all LHON cases are caused by the 1178G > A mutation of the mitochondrial deoxyribonucleic acid (mtDNA) (Cwerman-Thibault et al., 2014). There is an increasing body of evidence from genetic studies that mtDNA mutations and subsequent dysfunction may contribute to the pathogenesis of other debilitating ocular conditions including glaucoma (Lascaratos et al., 2012, Sundaresan et al., 2014) and age related macular degeneration (AMD) (Terluk et al., 2015). Also rarely oncocytomas (or oncocytic adenomas) may arise in the simple or glandular epithelia of the ocular adnexa (Jones et al., 2016). In this condition these cells demonstrate an eosinophilic appearance and excessive and abnormal mitochondria content (Østergaard et al., 2011).
Section snippets
Mitochondrial function in the healthy cornea
Mitochondria have a functional genome separate from that of nuclear DNA (Leonard and Schapira, 2000). The human mitochondrial genome is 16,569 bp long and forms a closed circular molecule (Anderson et al., 1981). Human mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes encode enzymes, which are crucial for the oxidative phosphorylation pathway required for the production of the majority of cellular adenosine triphosphate
Oxidative stress and the cornea
The cornea, given its highly exposed position, receives a significant amount of high-tension atmospheric oxygen and sunlight, including the ultraviolet range. These factors result in the generation of ROS and subsequent oxidative stress in the cornea (Wenk et al., 2001). Oxidative stress in the cornea is a consequence of an imbalance between Reactive oxygen species (ROS) production and the antioxidant capacity of the corneal cells (Choi et al., 2011). Reactive nitrogen species (RNS), especially
Antioxidants and the cornea
In the healthy cornea antioxidants such as superoxide dismutase, catalase, ascorbate and glutathione are present (Chwa et al., 2006, Spector et al., 2002, Yamada et al., 1991). Ascorbate (vitamin C) acts as a reducing agent and reacts rapidly with ROS, such as superoxide anion and hydroxyl radical, thereby protecting the cornea from oxidative stress (Zierhut et al., 2008). Ascorbate acts as a filter from UV light, which is required for the prevention of light induced damage (Ringvold et al.,
Corneal endothelial dysfunction in inherited mitochondrial disease
Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of mitochondrial dysfunction caused by mutation of either nuclear DNA or mitochondrial DNA. Many individuals with a mutation of mtDNA display a cluster of clinical features that fall into a discrete clinical syndrome (Chinnery, 2000). A corneal phenotype has been reported in Kearns-Sayre syndrome (KSS; MIM#530000) (Boonstra et al., 2002, Chang et al., 1994, Nakagawa et al., 1995, Ohkoshi et al., 1989
Mitochondrial dysfunction and oxidative stress in Fuchs endothelial corneal dystrophy
Fuchs endothelial corneal dystrophy (FECD) is a progressive, bilateral disease characterised by a gradual loss of corneal endothelial cells (CECs). Loss of CECs impairs the ability of the cornea to maintain hydration and results in a progressive decline in corneal transparency and hence a decline in vision (Bonanno, 2003, Elhalis et al., 2010). FECD is estimated to affect about 4% of the population, mostly in the fourth and fifth decade of life (Wojcik et al., 2013). In FECD there is an
Mitochondrial dysfunction and oxidative stress in keratoconus
Keratoconus is the leading cause of corneal transplantation in young people accounting for 25% of all transplants. Keratoconus affects around 1 in 2000 people in the United Kingdom. It is a lifelong condition, and is a significant health burden in work-age adults (Rabinowitz, 1998). The corneal thinning and protrusion due to keratoconus commences in teenage years with variable progression into mid-life, at which point it normally stabilises (see Fig. 4) (Rabinowitz, 1998). Clinically, the
Anti-oxidant and mitochondrial therapies for corneal disease
Corneal epithelial defects are commonly treated using agents known for their antioxidant properties e.g. ascorbate (vitamin C) (Boyd and Campbell, 1950, Gross, 2000, Saika et al., 1993). Other antioxidant agents such as Trolox® (a cell permeable, water soluble derivative of vitamin E) (Hallberg et al., 1996), vitamin E (Bilgihan et al., 2003) and superoxide dismutase derivatives e.g. an acylated SOD derivative (Ando et al., 1990) and lecithin bound superoxide dismutase (Shimmura et al., 2003)
Conclusion
This review demonstrates the increasing evidence of the role oxidative stress and subsequent mitochondrial dysfunction in the pathogenesis of both inherited and acquired corneal pathologies. The unique physiology of the cornea predisposes this structure to oxidative damage, and there is interplay between inherited and acquired mitochondrial dysfunction, oxidative damage and a number of corneal diseases. The imbalance of ROS and antioxidants can then result in mtDNA mutations which can play a
Acknowledgements
We kindly acknowledge the following individuals who supplied images:
Dr. Luciane Dreher Irion, Consultant Ophthalmic Histopathologist Central Manchester University Hospital (Fig. 1).
Dr. Bernhard Steger, Department Ophthalmology, Medical University of Innsbruck, Austria (Fig. 3).
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