GSSG

GSSG, or glutathione disulfide, is the oxidized form of glutathione. It is formed when two molecules of reduced glutathione (GSH) are linked by a disulfide bond during the neutralization of reactive oxygen species and other oxidants. In a healthy cell, GSSG is present at much lower levels than GSH, so the GSH/GSSG pair effectively buffers cellular redox changes.

The GSH/GSSG redox couple is central to maintaining thiol homeostasis. GSH acts as an adequate reductant, converting peroxides and other reactive species to non-reactive products and in the process becoming GSSG. Glutathione reductase reduces GSSG back to two GSH using NADPH as an electron donor, sustaining the intracellular pool of reduced glutathione. The ratio of GSH to GSSG is a sensitive indicator of cellular redox state; a decrease in this ratio reflects oxidative stress and can influence redox signaling and enzyme activities.

GSSG is primarily cytosolic but can be exported from cells via transporters such as multidrug resistance-associated proteins. Extracellular GSSG, though typically low, can be detected in plasma. GSSG also participates in S-glutathionylation, a reversible post-translational modification where GSH forms mixed disulfides with protein thiols, protecting them from irreversible oxidation and modulating signaling pathways. Reversal is facilitated by glutaredoxin systems, which regenerate free thiols and GSH.

Clinically, elevated GSSG levels or a decreased GSH/GSSG ratio are associated with aging and a range of diseases marked by oxidative stress, including neurodegenerative disorders, cardiovascular disease, diabetes, and liver injury. Measurements are commonly performed by high-performance liquid chromatography, mass spectrometry, or enzymatic recycling assays.