Molecular mechanisms of cadmium detoxification

Seminar

Title: Molecular mechanisms of cadmium detoxification using the biological model Saccharomyces cerevisiae

Speaker: Elis Eleutherio

Affiliation: UFRJ, Rio de Janeiro, Brazil

Host: Claudina Rodrigues-Pousada, Genomics and Stress Lab

Abstract

Cadmium (Cd) is a strong mutagen that acts by inhibiting DNA mismatch repair, while its toxic effect seems to be related to an indirect oxidative stress that involves glutathione (GSH) mobilization. Using Saccharomyces cerevisiae as experimental model, we have investigated the mechanisms of Cd tolerance in eukaryotes. By measuring the level of intracellular oxidation, lipid peroxidation, and protein oxidation, as well as the rate of mutagenesis, we have identified the molecular markers of cell damage responsible for Cd sensitivity. According to the literature, one general mechanism for Cd detoxification is the chelation of the metal by GSH. In mammals, GSH complex is pumped out of the cell by the multidrug resistance-associated protein, MRP, while in S. cerevisiae GSH-Cd complex is transported to vacuole through Ycf1, homologous to MRP. According to ours results, vacuolar transport of Cd-GSH complex is necessary to allow Cd tolerance, probably, because once inside the vacuole, the complex can be decomposed, initially by gamma-glutamyl transferase and thereafter by other peptidases, restoring the amino acids in the cytoplasm, which can be used to the synthesis denovo of GSH. Thus, the cytoplasmic GSH is recycled for the protection against metals, xenobiotics and oxidative stress. The presence of Cd-GSH complex in the cytoplasm increases the mutation rate, indicating that the compartmentation of Cd in the vacuole is crucial and determines the ability of the cells to survive metal toxicity.