FIG. 5.

Thiol transport between cell organelles and exchange between the intra- and extracellular compartments. In human plasma, aminothiols such as cysteine, homocysteine, and glutathione exist in free (reduced and oxidized) and protein-bound form, but little is known about the dynamics of their regulation and relationship with each other. As documented for cysteine and glutathione, aminothiols are transported across cell membranes and exchanged between cell organelles, with specific transporters such as the cystine (CysSSCys)/glutamate (Glu) antiporter (Xc), which plays an important role in the regulation of cell surface redox. Continuous arrows indicate known relationships, interrupted arrows represent unknown relationships. In both the intracellular and extracellular compartments, protein thiols represent the main pool of sulfhydryl (-SH) groups. (Note that different font sizes in the figure denote relative concentrations and that mixed disulfides of low-molecular-weight thiols and post-translational thiol modifications are omitted here for the sake of simplicity.) The cytosol is considerably more reduced compared with the extracellular space or the endoplasmic reticulum (where proper protein folding requires more oxidizing conditions). The redox couples, cysteine/cystine, GSH/GSSG, and protein-bound thiols, are not in equilibrium with each other, which suggests the involvement of specific enzyme systems that determine the steady-state levels of these species. Maintaining disequilibria requires energy, and energy tends to be allocated according to criteria that confer robustness of organisms along the evolutionary selection process. First steps into the direction of decoding what determines ATP utilization hierarchies at a systems level are being taken, but the mechanisms of regulation of systemic thiol/disulfide status remain largely obscure. Considering the inverse association of free thiols with risk of death, a further assessment of these relationships and their significance for the cellular stress responses, DNA repair processes, and other hard clinical endpoints seems to be justified. However, no number of observational studies will ever be able to establish causality; this will require prospective and interventional studies.