Glutathione revisited: a vital function in iron metabolism and ancillary role in thiol-redox control

Abstract

Glutathione contributes to thiol‐redox control and to extra‐mitochondrial iron–sulphur cluster (ISC) maturation. To determine the physiological importance of these functions and sort out those that account for the GSH requirement for viability, we performed a comprehensive analysis of yeast cells depleted of or containing toxic levels of GSH. Both conditions triggered an intense iron starvation‐like response and impaired the activity of extra‐mitochondrial ISC enzymes but did not impact thiol‐redox maintenance, except for high glutathione levels that altered oxidative protein folding in the endoplasmic reticulum. While iron partially rescued the ISC maturation and growth defects of GSH‐depleted cells, genetic experiments indicated that unlike thioredoxin, glutathione could not support by itself the thiol‐redox duties of the cell. We propose that glutathione is essential by its requirement in ISC assembly, but only serves as a thioredoxin backup in cytosolic thiol‐redox maintenance. Glutathione‐high physiological levels are thus meant to insulate its cytosolic function in iron metabolism from variations of its concentration during redox stresses, a model challenging the traditional view of it as prime actor in thiol‐redox control.