title: p53 orchestrates the PGC-1α-mediated antioxidant response upon mild redox and metabolic imbalance.
abstract: OBJECTIVE
  The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1 α (PPARGC1A or PGC-1α) 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-1α 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-1α 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-1α 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-1α upregulation is directed to potentiate the antioxidant defense through nuclear factor (erythroid-derived 2)-like2 (NFE2L2)-mediated expression of manganese superoxide dismutase (SOD2) and γ-glutamylcysteine ligase without modulating mitochondrial biogenesis.
  
  
  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.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Aquilano
authors.forename: Sara
authors.initials: S
authors.lastname: Baldelli
authors.forename: Beatrice
authors.initials: B
authors.lastname: Pagliei
authors.forename: Stefano M
authors.initials: SM
authors.lastname: Cannata
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rotilio
authors.forename: Maria R
authors.initials: MR
authors.lastname: Ciriolo
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis; D002460:Cell Line; D004790:Enzyme Induction; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000172:deficiency; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D015854:Up-Regulation; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D006360:Heat-Shock Proteins; D051267:NF-E2-Related Factor 2; D009569:Nitric Oxide; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013482:Superoxide Dismutase; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000099156:Superoxide Dismutase 2; C495635:NFE2L2 protein, human; C486497:PPARGC1A protein, human; C495901:TP53 protein, human