Connexin Gap Junctions and Hemichannels in Modulating Lens Redox Homeostasis and Oxidative Stress in Cataractogenesis

Abstract

The lens is continuously exposed to oxidative stress insults, such as ultraviolet radiation and other oxidative factors, during the aging process. The lens possesses powerful oxidative stress defense systems to maintain its redox homeostasis, one of which employs connexin channels. Connexins are a family of proteins that form: (1) Hemichannels that mediate the communication between the intracellular and extracellular environments, and (2) gap junction channels that mediate cell-cell communication between adjacent cells. The avascular lens transports nutrition and metabolites through an extensive network of connexin channels, which allows the passage of small molecules, including antioxidants and oxidized wastes. Oxidative stress-induced post-translational modifications of connexins, in turn, regulates gap junction and hemichannel permeability. Recent evidence suggests that dysfunction of connexins gap junction channels and hemichannels may induce cataract formation through impaired redox homeostasis. Here, we review the recent advances in the knowledge of connexin channels in lens redox homeostasis and their response to cataract-related oxidative stress by discussing two major aspects: (1) The role of lens connexins and channels in oxidative stress and cataractogenesis, and (2) the impact and underlying mechanism of oxidative stress in regulating connexin channels.

Role and Posttranslational Regulation of Cx46 Hemichannels and Gap Junction Channels in the Eye Lens

“…An association between connexins, redox potential and oxidative stress is well established ( Quan et al, 2021 ; Zhang et al, 2021 ), although low or physiological levels NO could have a protective effect in lens epithelial cells ( Chamberlain et al, 2008 ). A high production of NO in human lens has been associated with cataracts, especially in hypertensive patients ( Ornek et al, 2003 ) and smokers ( Anitha et al, 2019 ), and a similar association has been found in animal models of hypertension and diabetes ( Abdul Nasir et al, 2017 ; Yadav et al, 2018 ).…”

Physiological Mechanisms Regulating Lens Transport

“…The permeability and transport properties of these channels are implicated in lens epithelial growth and proliferation, Na + and water coupled transport, Ca 2+ transport, antioxidant gradients, and second messenger permeability ( Mathias et al, 2010 ; Slavi et al, 2014 ; Brink et al, 2020 ). One important nutrient that connexin channels circulate is the tripeptide glutathione (GSH), which is the main alleviator of oxidative stress in lens fiber cells ( Slavi et al, 2014 ; Braakhuis et al, 2019 ; Quan et al, 2021 ). The role of connexin channels in the lens has been primarily established using genetic knock-out (KO) and knock-in (KI) models ( Berthoud et al, 2014 ).…”

“…Age and oxidative stress in the lens are usually coincident and lead to changes in the lens proteome, including connexin channel density and regulation ( Gao et al, 2013 ; Gong et al, 2021 ; Quan et al, 2021 ). The lens is protected from oxidative damage by antioxidants, such as GSH, and chaperone proteins to prevent protein aggregation and dissolution from oxidative stress ( Giblin, 2000 ; Lim et al, 2020 ).…”

“…However, the mechanism of how GSSG is removed from the nucleus is still unknown, but is predicted to also work through passive diffusion to the surface cells or breakdown in the nucleus directly ( Slavi et al, 2014 ). Connexin hemichannels opened in response to H 2 O 2 , mechanical stress, or ultraviolet radiation and allowed transit of glucose, GSH, and H 2 O 2 ( Liu et al, 2020 ; Quan et al, 2021 ). These results suggested that connexin hemichannels may also play a key role in maintaining the metabolic and antioxidative function of the lens, through facilitation of direct exchange of nutrients and redox metabolites between the extracellular space and cytoplasm.…”

Thioredoxin‐1 regulates the autophagy induced by oxidative stress through LC3‐II in human lens epithelial cells

“…Substantial evidence has shown that aggravated oxidative stress in the lens epithelial cells (LECs) layer is a vital initiation factor in cataract formation 5 . Previous studies have also indicated that exposure to environmental risk factors produces reactive oxygen species (ROS) which can disrupt the redox balance of LECs 6 resulting in oxidation of lens proteins, DNA damage and/or lipid peroxidation, all of which have been implicated in formation lens opacity 7…”