p53 Orchestrates the PGC-1α-Mediated Antioxidant Response Upon Mild Redox and Metabolic Imbalance

Abstract

Aims: The transcriptional coactivator peroxisome proliferator-activated receptor-c coactivator-1 a (PPARGC1A or PGC-1a) is a powerful controller of cell metabolism and assures the balance between the production and the scavenging of pro-oxidant molecules by coordinating mitochondrial biogenesis and the expression of antioxidants. However, even though a huge amount of data referring to the role of PGC-1a is available, the molecular mechanisms of its regulation at the transcriptional level are not completely understood. In the present report, we aim at characterizing whether the decrease of antioxidant glutathione (GSH) modulates PGC-1a expression and its downstream metabolic pathways. Results: We found that upon GSH shortage, induced either by its chemical depletion or by metabolic stress (i.e., fasting), p53 binds to the PPARGC1A promoter of both human and mouse genes, and this event is positively related to increased PGC-1a expression. This effect was abrogated by inhibiting nitric oxide (NO) synthase or guanylate cyclase, implicating NO/cGMP signaling in such a process. We show that p53-mediated PGC-1a upregulation is directed to potentiate the antioxidant defense through nuclear factor (erythroid-derived 2)-like2 (NFE2L2)-mediated expression of manganese superoxide dismutase (SOD2) and c-glutamylcysteine ligase without modulating mitochondrial biogenesis. Innovation and Conclusions: We outlined a new NO-dependent signaling axis responsible for survival antioxidant response upon mild metabolic stress (fasting) and/or oxidative imbalance (GSH depletion). Such signaling axis could become the cornerstone for new pharmacological or dietary approaches for improving antioxidant response during ageing and human pathologies associated with oxidative stress. Antioxid. Redox Signal. 18, 386-399.

The role of nNOS and PGC-1α in skeletal muscle cells

“…In particular, caloric restriction increases both eNOS and nNOS activity (Nisoli et al, 2005;Fusco et al, 2012). In our laboratory, we have shown that, in skeletal muscle, caloric restriction also increases NO bioavailability independently of NOS upregulation (Aquilano et al, 2013a). In particular, caloric restriction reduces the level of GSH, the main intracellular NO buffer (Aquilano et al, 2011a;Aquilano et al, 2011b;Baldelli et al, 2008).…”

“…In particular, caloric restriction reduces the level of GSH, the main intracellular NO buffer (Aquilano et al, 2011a;Aquilano et al, 2011b;Baldelli et al, 2008). The resulting increased NO bioavailability is the genuine mediator of the upregulation of PGC-1a, which, in turn, favours the expression of antioxidant proteins SOD2 and c-GCS (also known as glutamate cysteine ligase) (Aquilano et al, 2013a).…”

mTOR plays a critical role in p53-induced oxidative kidney cell injury in HIVAN

“…p53 has been reported to be the modulator of oxidative stress-it downregulates low oxidative stress and exacerbates higher levels of stresses (22). For example, at low levels of oxidative stress, p53 activates antioxidant genes such as sestrin and glutathione peroxidase (1,6,16). Additionally, p53 induces the expression of TP53-induced glycolysis and apoptosis regulator, which slows glycolysis and promotes the production of NADPH to decrease ROS levels (50).…”

Nuclear Recruitment of Neuronal Nitric-oxide Synthase by α-Syntrophin Is Crucial for the Induction of Mitochondrial Biogenesis

“…After treatment, oligonucleotide pulldown assay was carried out as described previously (40) by using the cAMP response element sequence on the mouse PGC-1␣ gene (ppargc1a) promoter (supplemental Table S1). Oligonucleotide pulldown specificity was demonstrated with mutant oligonucleotides used as negative controls (data not shown).…”