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.

Chrysin Reduces Oxidative Stress but Does Not Affect Polyol Pathway in the Lenses of Type 1 Diabetic Rats

“…This statistically significant effect could not simply be explained by counteracting the diabetic state. Usually GSH is synthetized in the lens epithelial cells and outer cortex, but can also be transported from aqueous humor or be restored from GSSG [63,64]. However, GSH synthesis may also be promoted by flavonoid supplementation.…”

Signaling and Gene Regulatory Networks in Mammalian Lens Development

“…The main cytoplasm building materials are the lens-preferred α- and β/γ-crystallin proteins [319]. Lens also contains high concentrations of reduced glutathione (GST) to provide protection against membrane and protein oxidation [320]. …”

Glutathione: subcellular distribution and membrane transport

“…The first major insights into glutathione transport and organismal glutathione distribution were gained in studies spanning the early 1960s to the late 1990s. Evidence for cellular export and import of GSH, GSSG and glutathione conjugates came from a range of cell types, including, but not limited, to hepatocytes, renal proximal tubular cells, intestinal epithelial cells, erythrocytes, astrocytes and retinal epithelial cells (Ballatori and Dutczak 1994;Chen et al 2000;Fan et al 2017;Iantomasi et al 1997;Lash 2005Lash , 2009Lee et al 1997;Minich et al 2006;Muller et al 1996;Prchal et al 1975;Reddy et al 1973). These observations suggest that transporters capable of mediating the export and perhaps the import of glutathione species across the plasma membrane are present in most mammalian cell types.…”