This may NVP-BEZ235 PI3K inhibitor explain the discrepancy between the frequency of common SCAD variations in the general population, and the prevalence of clinically manifest SCADD. The vulnerability to oxidative stress appears to be independent of the ACADS genotype, concordant with previous reports of inconsistent genotype-phenotype correlations. A further example is the contrasting clinical phenotypes of c.625G.A homozygosity which may be explained by our recent description of decreased SOD2 expression in the affected patient vs ��asymptomatic control�� fibroblasts. In addition, exogenous stressors, such as VE-822 ATM/ATR inhibitor hypoglycemia and fever, may influence the clinical phenotype. Oxidative stress with hydrogen peroxide, under heat stress, has been shown to impair the heat stress response, delay unfolded protein recovery and enhance loss of mitochondrial membrane potential. In mitochondrial Complex I deficiency with the cardiomyopathy and cataracts phenotype, it has been proposed that significant induction of SOD2 may result from a temporarily much elevated superoxide production rate in the presence of an abnormally reduced redox state, as occurs in anoxia reperfusion injury. Superoxide specifically attacks centres in Complex I and II resulting in release of free iron in mitochondria and cytosol, which generates excessive OH2. This could be the mechanism in our SCADD fibroblasts, with exacerbation by heat stress due to protein unfolding. Oxidative stress is likely to trigger pro-apoptotic signaling cascades. Of the 7 glutathione peroxidases in mammals, GPx4 is specific for phospholipid hydroperoxides in membranes, and is shown to be significant for neuronal survival. GPx4 senses and translates oxidative stress into a 12/15-lipoxygenase dependent- and apoptosis-inducing factor-mediated cell death pathway. In GPx4-knockout cells, lipid peroxidative injury was the key mediator of cell death and was efficiently prevented by Vitamin E. Vitamins E and C have been reported to neutralize free radicals. We evaluated these effects at physiological plasma concentrations.