Abstract
The cystine/glutamate antiporter (system xc−) is composed of a heavy chain subunit 4F2hc linked by a disulphide bond to a light chain xCT, which exchanges extracellular cystine, the disulphide form of the amino acid cysteine, for intracellular glutamate. In vitro research in the brain, kidney, and liver have shown this antiporter to play a role in minimising oxidative stress by providing a source of intracellular cysteine for the synthesis of the antioxidant glutathione. In vivo studies using the xCT knockout mouse revealed that the plasma cystine/cysteine redox couple was tilted to a more oxidative state demonstrating system xc− to also play a role in maintaining extracellular redox balance by driving a cystine/cysteine redox cycle. In addition, through import of cystine, system xc− also serves to export glutamate into the extracellular space which may influence neurotransmission and glutamate signalling in neural tissues. While changes to system xc− function has been linked to cancer and neurodegenerative disease, there is limited research on the roles of system xc− in the different tissues of the eye, and links between the antiporter, aging, and ocular disease. Hence, this review seeks to consolidate research on system xc− in the cornea, lens, retina, and ocular humours conducted across several species to shed light on the in vitro and in vivo roles of xCT in the eye and highlight the utility of the xCT knockout mouse as a tool to investigate the contribution of xCT to age-related ocular diseases.
Highlights
The cystine/glutamate exchanger, referred to as system xc, is responsible for the Na+-independent electroneutral exchange of cystine and glutamate [1]. It is a member of the heteromeric amino acid transporter family and is composed of a heavy subunit 4F2hc (SLC3A2) that is involved in the trafficking of the heterodimer to the plasma membrane, and a light subunit xCT (SLC7A11), which is responsible for the exchange of extracellular cystine for intracellular glutamate [2]
System xc- has been shown to be a major source of cysteine, the rate limiting amino acid required for GSH synthesis, suggesting that upregulation of system xccould help to restore cysteine and/or GSH levels, preventing or slowing down the progression of ocular pathologies initiated by oxidative damage [8,9,10,11,12,13,14,15]
In studies of mouse retinal ganglion cells, nitric oxide and reactive oxygen species were shown to upregulate system xc- via an increase in xCT mRNA expression and protein levels which resulted in a concomitant increase in GSH [16]
Summary
The cystine/glutamate exchanger, referred to as system xc-, is responsible for the Na+-independent electroneutral exchange of cystine and glutamate [1] It is a member of the heteromeric amino acid transporter family and is composed of a heavy subunit 4F2hc (SLC3A2) that is involved in the trafficking of the heterodimer to the plasma membrane, and a light subunit xCT (SLC7A11), which is responsible for the exchange of extracellular cystine for intracellular glutamate [2]. System xc- has been shown to be a major source of cysteine, the rate limiting amino acid required for GSH synthesis, suggesting that upregulation of system xccould help to restore cysteine and/or GSH levels, preventing or slowing down the progression of ocular pathologies initiated by oxidative damage [8,9,10,11,12,13,14,15]. The potential utility of system xc- in influencing antioxidant homeostasis and glutamate signalling pathways in ocular tissues is relevant
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