Evidence of altered redox homeostasis in trichothiodystrophy

Objective: Trichothiodystrophy (TTD) is a rare hereditary disease whose prominent feature is brittle hair. Additional clinical signs are physical and neurodevelopmental abnormalities and in about half of the cases hypersensitivity to UV radiation. Although the mutations involved in this condition have been characterized, the correlation between the molecular defects and the plethora of clinical symptoms is not well understood. Recently, the presence of a redox imbalance in TTD has been suggested although no clear evidence has been reported on this aspect. Methods: In the present study, we evaluated the redox status of fibroblasts isolated from a TTD patient. In addition, to understand the ability of TTD cells to respond to oxidative insults, the cells were challenged with H2O2. Mitochondrial O2•− and mitochondrial membrane potential were measured in different oxidative conditions. In addition, protein levels of NRF2 and BACH1 were also analyzed in response to H2O2. Results: The results suggested an aberrant mitochondrial response to oxidative stimuli, an increased baseline oxidative stress status in TTD, and an altered NRF2/BACH1 level. Conclusions: This study emphasizes the altered redox homeostasis in TTD pathogenesis and mitochondria functionality. Significance statement Focusing on mitochondria homeostasis and redox imbalance could represent an alternative therapeutic target for this condition to improve patients’ clinical features.