Lens glutathione homeostasis: Discrepancies and gaps in knowledge standing in the way of novel therapeutic approaches

Abstract

Cataract is the major cause of blindness worldwide. The WHO has estimated around 20 million people have bilateral blindness from cataract, and that number is expected to reach 50 million in 2050. The cataract surgery is currently the main treatment approach, though often associated with complications, such as Posterior Capsule Opacification (PCO)-also known as secondary cataract. The lens is an avascular ocular structure equipped with an unusually high level of glutathione (GSH), which plays a vital role in maintaining lens transparency by regulating lenticular redox state. The lens epithelium and outer cortex are thought to be responsible for providing the majority of lens GSH via GSH de novo synthesis, assisted by a continuous supply of constituent amino acids from the aqueous humor, as well as extracellular GSH recycling from the gamma-glutamyl cycle. However, when de novo synthesis is impaired, in the presence of low GSH levels, as in the aging human lens, compensatory mechanisms exist, suggesting that the lens is able to uptake GSH from the surrounding ocular tissues. However, these uptake mechanisms, and the GSH source and its origin, are largely unknown. The lens nucleus does not have the ability to synthesize its own GSH and fully relies on transport from the outer cortex by yet unknown mechanisms. Understanding how aging reduces GSH levels, particularly in the lens nucleus, how it is associated with age-related nuclear cataract (ARNC), and how the lens compensates for GSH loss via external uptake should be a major research priority. The intent of this review, which is dedicated to the memory of David C. Beebe, is to summarize our current understanding of lens GSH homeostasis and highlight discrepancies and gaps in knowledge that stand in the way of pharmacologically minimizing the impact of declining GSH content in the prevention of age-related cataract.

Keywords: Aging; Cataract; Glutathione; Homeostasis; Lens; Transporter.

Figure 1. Lens glutathione homeostasis

(Top panel): Illustration of the lens and its conjunction ocular tissues. The ciliary body with its vascular circulation system continuously produces the aqueous humor that contains both the constituent amino acids for GSH synthesis and GSH/GSSG. It first enters the posterior chamber, then reaches to the anterior aqueous humor and then drains out via trabecular meshwork and Shclemm’s canal. Both ciliary body and retina also produce molecular solute into the vitreous humor to maintain vitreous humor in a more dynamic, and this may also include GSH and GSSG. The lens will then utilize the amino acids, GSH or GSSG supply to maintain its GSH homeostasis via de novo synthesis and uptake, respectively. The pathway with a question marker indicates that it is currently unknown. (Lower left panel): The illustration of lens structure. The anterior of the lens is assembled with monolayer of epithelial cells, and their continuously proliferation and differentiation produce lens fiber cells to form outer and inner cortical fiber layer. The lens nucleus is assembled with the embryonic nucleus and the fetal nucleus. The lens epithelial cells and outer cortical fiber cells have the ability to synthesis GSH, while lens nuclear GSH is completely reliant on transport from outer cortex. The outer cortex has been found possess high concentration of GSH than lens nucleus, though whether this is also true in posterior outer cortex is still unclear. (Lower right panel): Illustration of lens epithelial and outer fiber layer. The epithelial cells are responsible for transporting the constituent amino acids from aqueous humor for GSH synthesis, which is taking place in both epithelial and outer fiber cell layer. The lens epithelial cells may also take up GSH or GSSG from aqueous humor. The high GSH concentration gradient between lens and aqueous humor implicates it might be a carried based transporting mechanisms, though the identity of the transporter is still unknown. The lens fiber cells are enriched with gap junctions, and it has been suggested that gap junction might playing a role in lens nuclear GSH homeostasis.