Charcot-Marie-Tooth (CMT) disease is a common inherited peripheral neuropathy. The CMT2K axonal form is associated with GDAP1 dominant mutations, which according to the affected domain cause a gradient of severity. Indeed, the p.C240Y mutation, located within GDAP1 glutathione S-transferase (GST) domain and associated to a mitochondrial complex I defect, is related to a faster disease progression, compared to other mutations, such as the p.R120W located outside the GST domain. Here, we analysed the pathophysiology of six CMT2K fibroblast cell lines, carrying either the p.C240Y or p.R120W mutations. We show that complex I deficiency leads to a redox potential alteration and a significant reduction of sirtuin 1 (SIRT1) expression, a major deacetylase sensitive to the cellular redox state, and NRF1 the downstream target of SIRT1. In addition, we disclosed that the p.C240Y mutation is associated with a greater mitochondrial oxidative stress than the p.R120W mutation. Moreover, complex I activity is further restored in CMT2K mutant cell lines exposed to resveratrol. Together, these results suggest that the reduction of oxidative stress may constitute a promising therapeutic strategy for CMT2K.
Keywords: Charcot-Marie-Tooth; Complex I; GDAP1; Mitochondria; Oxidative stress.
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