Cargando…

Effects of Deacetylase Inhibition on the Activation of the Antioxidant Response and Aerobic Metabolism in Cellular Models of Fanconi Anemia

Fanconi anemia (FA) is a rare genetic disease characterized by a dysfunctional DNA repair and an oxidative stress accumulation due to defective mitochondrial energy metabolism, not counteracted by endogenous antioxidant defenses, which appear down-expressed compared to the control. Since the antioxi...

Descripción completa

Detalles Bibliográficos
Autores principales: Bertola, Nadia, Regis, Stefano, Bruno, Silvia, Mazzarello, Andrea Nicola, Serra, Martina, Lupia, Michela, Sabatini, Federica, Corsolini, Fabio, Ravera, Silvia, Cappelli, Enrico
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215951/
https://www.ncbi.nlm.nih.gov/pubmed/37237966
http://dx.doi.org/10.3390/antiox12051100
_version_ 1785048185139363840
author Bertola, Nadia
Regis, Stefano
Bruno, Silvia
Mazzarello, Andrea Nicola
Serra, Martina
Lupia, Michela
Sabatini, Federica
Corsolini, Fabio
Ravera, Silvia
Cappelli, Enrico
author_facet Bertola, Nadia
Regis, Stefano
Bruno, Silvia
Mazzarello, Andrea Nicola
Serra, Martina
Lupia, Michela
Sabatini, Federica
Corsolini, Fabio
Ravera, Silvia
Cappelli, Enrico
author_sort Bertola, Nadia
collection PubMed
description Fanconi anemia (FA) is a rare genetic disease characterized by a dysfunctional DNA repair and an oxidative stress accumulation due to defective mitochondrial energy metabolism, not counteracted by endogenous antioxidant defenses, which appear down-expressed compared to the control. Since the antioxidant response lack could depend on the hypoacetylation of genes coding for detoxifying enzymes, we treated lymphoblasts and fibroblasts mutated for the FANC-A gene with some histone deacetylase inhibitors (HDACi), namely, valproic acid (VPA), beta-hydroxybutyrate (OHB), and EX527 (a Sirt1 inhibitor), under basal conditions and after hydrogen peroxide addition. The results show that VPA increased catalase and glutathione reductase expression and activity, corrected the metabolic defect, lowered lipid peroxidation, restored the mitochondrial fusion and fission balance, and improved mitomycin survival. In contrast, OHB, despite a slight increase in antioxidant enzyme expressions, exacerbated the metabolic defect, increasing oxidative stress production, probably because it also acts as an oxidative phosphorylation metabolite, while EX527 showed no effect. In conclusion, the data suggest that VPA could be a promising drug to modulate the gene expression in FA cells, confirming that the antioxidant response modulation plays a pivotal in FA pathogenesis as it acts on both oxidative stress levels and the mitochondrial metabolism and dynamics quality.
format Online
Article
Text
id pubmed-10215951
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-102159512023-05-27 Effects of Deacetylase Inhibition on the Activation of the Antioxidant Response and Aerobic Metabolism in Cellular Models of Fanconi Anemia Bertola, Nadia Regis, Stefano Bruno, Silvia Mazzarello, Andrea Nicola Serra, Martina Lupia, Michela Sabatini, Federica Corsolini, Fabio Ravera, Silvia Cappelli, Enrico Antioxidants (Basel) Article Fanconi anemia (FA) is a rare genetic disease characterized by a dysfunctional DNA repair and an oxidative stress accumulation due to defective mitochondrial energy metabolism, not counteracted by endogenous antioxidant defenses, which appear down-expressed compared to the control. Since the antioxidant response lack could depend on the hypoacetylation of genes coding for detoxifying enzymes, we treated lymphoblasts and fibroblasts mutated for the FANC-A gene with some histone deacetylase inhibitors (HDACi), namely, valproic acid (VPA), beta-hydroxybutyrate (OHB), and EX527 (a Sirt1 inhibitor), under basal conditions and after hydrogen peroxide addition. The results show that VPA increased catalase and glutathione reductase expression and activity, corrected the metabolic defect, lowered lipid peroxidation, restored the mitochondrial fusion and fission balance, and improved mitomycin survival. In contrast, OHB, despite a slight increase in antioxidant enzyme expressions, exacerbated the metabolic defect, increasing oxidative stress production, probably because it also acts as an oxidative phosphorylation metabolite, while EX527 showed no effect. In conclusion, the data suggest that VPA could be a promising drug to modulate the gene expression in FA cells, confirming that the antioxidant response modulation plays a pivotal in FA pathogenesis as it acts on both oxidative stress levels and the mitochondrial metabolism and dynamics quality. MDPI 2023-05-15 /pmc/articles/PMC10215951/ /pubmed/37237966 http://dx.doi.org/10.3390/antiox12051100 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bertola, Nadia
Regis, Stefano
Bruno, Silvia
Mazzarello, Andrea Nicola
Serra, Martina
Lupia, Michela
Sabatini, Federica
Corsolini, Fabio
Ravera, Silvia
Cappelli, Enrico
Effects of Deacetylase Inhibition on the Activation of the Antioxidant Response and Aerobic Metabolism in Cellular Models of Fanconi Anemia
title Effects of Deacetylase Inhibition on the Activation of the Antioxidant Response and Aerobic Metabolism in Cellular Models of Fanconi Anemia
title_full Effects of Deacetylase Inhibition on the Activation of the Antioxidant Response and Aerobic Metabolism in Cellular Models of Fanconi Anemia
title_fullStr Effects of Deacetylase Inhibition on the Activation of the Antioxidant Response and Aerobic Metabolism in Cellular Models of Fanconi Anemia
title_full_unstemmed Effects of Deacetylase Inhibition on the Activation of the Antioxidant Response and Aerobic Metabolism in Cellular Models of Fanconi Anemia
title_short Effects of Deacetylase Inhibition on the Activation of the Antioxidant Response and Aerobic Metabolism in Cellular Models of Fanconi Anemia
title_sort effects of deacetylase inhibition on the activation of the antioxidant response and aerobic metabolism in cellular models of fanconi anemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215951/
https://www.ncbi.nlm.nih.gov/pubmed/37237966
http://dx.doi.org/10.3390/antiox12051100
work_keys_str_mv AT bertolanadia effectsofdeacetylaseinhibitionontheactivationoftheantioxidantresponseandaerobicmetabolismincellularmodelsoffanconianemia
AT regisstefano effectsofdeacetylaseinhibitionontheactivationoftheantioxidantresponseandaerobicmetabolismincellularmodelsoffanconianemia
AT brunosilvia effectsofdeacetylaseinhibitionontheactivationoftheantioxidantresponseandaerobicmetabolismincellularmodelsoffanconianemia
AT mazzarelloandreanicola effectsofdeacetylaseinhibitionontheactivationoftheantioxidantresponseandaerobicmetabolismincellularmodelsoffanconianemia
AT serramartina effectsofdeacetylaseinhibitionontheactivationoftheantioxidantresponseandaerobicmetabolismincellularmodelsoffanconianemia
AT lupiamichela effectsofdeacetylaseinhibitionontheactivationoftheantioxidantresponseandaerobicmetabolismincellularmodelsoffanconianemia
AT sabatinifederica effectsofdeacetylaseinhibitionontheactivationoftheantioxidantresponseandaerobicmetabolismincellularmodelsoffanconianemia
AT corsolinifabio effectsofdeacetylaseinhibitionontheactivationoftheantioxidantresponseandaerobicmetabolismincellularmodelsoffanconianemia
AT raverasilvia effectsofdeacetylaseinhibitionontheactivationoftheantioxidantresponseandaerobicmetabolismincellularmodelsoffanconianemia
AT cappellienrico effectsofdeacetylaseinhibitionontheactivationoftheantioxidantresponseandaerobicmetabolismincellularmodelsoffanconianemia