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

INTRODUCTION: 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. Human CS cells present an altered redox balance and excessive mitochondrial fission due to hyper-phosphorylation of the mitochondrial fission protein Drp1 (1,2). MATERIAL & METHODS: Transformed fibroblasts were treated with mitochondrial uncoupler CCCP and mitochondria morphology analysed by live fluorescence experiments in TMRE-loaded cells. ROS species characterization was performed by EPR. The effect of MDIVI, a mitochondrial fission inhibitor, was studied by immunofluorescence experiments. RESULTS: We report that MDIVI is able to rescue the dysfunctional mitochondrial phenotype of CS-A cells, and plays also an anti-apoptotic role by reducing the translocation of Bax at mitochondria. Moreover, we show that CS cells are characterized by the formation of higher levels of nitric oxide (NO) and superoxide anion compared to normal fibroblasts. CONCLUSION: NO production is essential for S-nitrosylation and dysregulated S-nitrosylation could contribute to the development of neurodegenerative disorders. The study of post-translational modifications of mitochondrial proteins could contribute to the molecular characterization of the pathological features of CS and highlight Drp1 as a possible novel therapeutic target.