The effect of short-term methionine restriction on glutathione synthetic capacity and antioxidant responses at the whole tissue and mitochondrial level in the rat liver.

Abstract

Dietary methionine restriction (MR) where methionine is the sole source of sulfur amino acid increases lifespan in diverse species. Methionine restricted rodents experience a decrease in glutathione (GSH), a major antioxidant, in several tissues, which is paradoxical to longevity interventions because tissues with low GSH might experience more oxidative damage. Liver plays a key role in GSH synthesis and here we examined how MR influences GSH metabolism in the liver. We also hypothesised that low GSH might be subsidized by compensatory pathway(s) in the liver. To investigate GSH synthesis and antioxidant responses, Fischer-344 rats were given either a MR diet or a control diet for 8 weeks. Based on γ-glutamylcysteine synthetase activity, GSH synthetic capacity did not respond to low dietary methionine availability. Tissue level protein and lipid oxidation markers do not support elevated oxidative damage, despite low GSH availability. Whole tissue and mitochondrial level responses to MR differed. Specifically, the activity of glutathione reductase and thioredoxin reductase increase in whole liver tissue which might offset the effects of declined GSH availability whereas mitochondrial GSH levels were unperturbed by MR. Moreover, enhanced proton leak in liver mitochondria by MR (4 week) presumably diminishes ROS production. Taken together, we suggest that the effect of low GSH in liver tissue is subsidized, at least in part, by increased antioxidant activity and possibly by enhanced mitochondrial proton leak.