Redox imbalance activates PGC-1α-mediated mitochondrial antioxidant response during metabolic stress

Glutathione (GSH) is the most abundant low molecular weight thiol in mammalian cells and acts as the major cellular non-enzymatic antioxidant. GSH also has a pivotal function in buffering the intracellular production of nitric oxide (NO), particularly in brain wherein NO acts as an important neuromodulator and neurotransmitter. We have found that nutrient limitation, a dietary regimen that is generally linked to longevity, is associated with a decline of GSH level in mouse brain. This event is the primum movens of NO-mediated induction of the transcriptional co-activator peroxisome proliferator-activated receptor γ coactivator 1 α (PPARGC1A or PGC-1α) via a novel pathway involving p53. We have demonstrated that such pathway culminates in the enhancement of the mitochondrial antioxidant response (i.e. SOD2 increase) through the nuclear factor (erythroid-derived 2)-like2 (NFE2L2). Moreover, the pharmachological depletion of GSH results in the activation of such antioxidant pathway in the brain. Overall our results suggest that the decline of GSH level occurring with normal ageing and upon nutrient limitation could be a beneficial rather than a detrimental event and may serve as a molecular signal for adaptation to environmental/pathological stress and possibly in the extension of lifespan.