Disorders of Redox Homeostasis and Its Importance in Acrolein Toxicity

The maintenance of intracellular redox homeostasis depends on the GSH/GSSG pair, which is the primary intracellular redox buffer. However, the NADPH/NADP+ pair also plays a vital role in this process. The primary source of NADPH is the pentose phosphate pathway and deficiency in the enzymes responsible for NADPH production in this pathway leads to developing of alternative NADPH supply strategies. The choice of compensation strategy has several consequences for cells physiology. The present study investigates how Saccharomyces cerevisiae yeast strains defective in generating NADPH via the pentose phosphate pathway due to deletion of ZWF1, GND1, or GND2 genes, respond to redox homeostasis disruption caused by allyl alcohol, a metabolic precursor of acrolein. Acrolein is a highly reactive aldehyde that rapidly depletes glutathione and triggers oxidative stress. Therefore, cells respond to acrolein through attempts to increase glutathione synthesis, but also by increasing NADPH production. The response requires coordinated action of glutathione- and NADPH-dependent systems. The high sensitivity of the Δgnd1 strain, which is unable to activate an adequate stress response, is evidence of this. The strategy employed by this strain to maintain redox homeostasis is inadequate and may even exacerbate allyl alcohol toxicity.