Journal
ANTIOXIDANTS
Volume 12, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/antiox12051100
Keywords
catalase; glutathione reductase; oxidative phosphorylation; lipid peroxidation; aldehyde dehydrogenase; energy metabolism; antioxidant defenses; histone deacetylase inhibitors
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Fanconi anemia (FA) is a rare genetic disease characterized by dysfunctional DNA repair and oxidative stress accumulation. Histone deacetylase inhibitors (HDACi) can correct the metabolic defect and improve oxidative stress levels and mitochondrial dynamics quality. Sodium valproate (VPA) shows promise as a potential treatment drug.
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.
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