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.
Post-translational modifications of Drp1 link mitochondrial dysfunction to neurodegenerative features in Cockayne Syndrome A cells
Barbara Pascucci;
2018
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.