Glutathione: A cellular barricade against toxic metabolites

MORELLATO, AGUSTÍN E.; BUENO-COSTA, ALBERTO; CARLA UMANSKY; ESTELLER, MANEL; LUCAS PONTEL

Sussex

Simposio; Symposium: Toxic Metabolites in Disease; 2022

The Company of Biologist

Cells are continuously exposed to electrophilic metabolites that can avidly react with electron-rich groups present in vital biomolecules. One of the most abundant cellular electron-rich molecules is the antioxidant glutathione (GSH). GSH can reach millimolar levels in the cytosol, suggesting it could act as a first barrier against toxic metabolites by directly reducing their effective concentrations and thus their toxicity. To address this hypothesis, we first evaluated whether GSH synthesis is essential for the growth of cancer cell lines from different origins. We identified that acute-lymphoblastic leukaemia (ALL) cells depend on GSH synthesis because they epigenetically silence the expression of a GSH-independent factor that counteract ferroptosis, an iron-dependent form of cell death. Next, we reasoned that this selective dependency of ALL cells on GSH synthesis might also impact on the tolerance to cellular aldehydes. The detoxification of formaldehyde is mainly carried out by alcohol dehydrogenase 5 (ADH5). This enzyme requires the initial formation of the GSH-formaldehyde adduct termed S-hydroxy-methyl-GSH (HSMGSH). To address whether GSH can protect cells from formaldehyde independently of ADH5, we measured the formaldehyde tolerance in cancer cells from hematopoietic and non-hematopoietic lineages in presence of the pharmacological inhibitor of GSH synthesis. Our results identified that GSH can act as a barrier against formaldehyde in cells from hematopoietic origin. In these models, blocking ADH5 and GSH synthesis further increased formaldehyde toxicity. In contrast, in non-hematopoietic cancer cells, GSH synthesis was epistatic to ADH5 for FA tolerance, with ADH5 appearing as the dominant factor in formaldehyde tolerance. GSH is a major cellular antioxidant and functions as a co-factor of peroxidases involved in the detoxification of lipid and cellular peroxides. Our data indicate that formaldehyde can induce the accumulation of cellular peroxides, suggesting that a GSH-dependent peroxidase might protect cells from formaldehyde independently of ADH5.