Post-translational modifications of Drp1 link mitochondrial dysfunction to neurodegenerative features in Cockayne Syndrome A cells

A growing body of evidence indicate that the neurological defects in Cockayne Syndrome (CS) may be due to loss of mitochondrial function, whereas the impaired transcription-coupled repair could account for the skin photosensitivity. Evidence has been provided that human CS cells present an altered redox balance with increased steady-state levels of intracellular ROS, mitochondrial fragmentation and excessive fission due ti hyperphosphorylation of DRP1 (Pascucci et al., 2012; Pascucci et al., 2016). Here, we report that MDIVI, a mitochondrial fission inhibitor, is able to rescue the dysfunctional mitochondrial phenotype observed in CS, and plays also an anti-apoptotic role by reducing the traslocation of Bax at mitochondria in CS-A cells. These findings suggests that Drp1 could be a novel therapeutic target. Moreover, we show that CS cells are characterized by higher level of nitric oxide (NO) as compared to normal fibroblasts. Notably, NO production is essential for S-nitrosylation and dysregulated S-nitrosylation could contribute to the development of several neurodegenerative disorders. Therefore, the role of NO on the pathological features of CS is under investigation.