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 and excessive mitochondrial fission due to hyper-phosphorylation of the mitochondrial fission protein (Drp1)(Pascucci et al.; 2012, 2016). Since we found that pDRP1 and CSA localize at mitochondria after mitochondrial damage, we wondered if DRP1 inhibition was capable to rescue the CSA pathological phenotype. When enzymatic activity of DRP1 is inhibited by MDVI, a mitochondrial fission inhibitor, the high ROS levels are reduced, and the dysfunctional mitochondrial, apoptotic phenotype of CS-A cells is recovered. Moreover, CS-A cells present a significant reduction of nitric oxide (NO) levels respect to WT fibroblasts and interestingly, CS-A cells are characterized by an overexpression of the S-nitrosoglutathione reductase, suggesting for the first time that nitrosative stress might play a role in CS. All these preliminary data clearly indicate that the modulation of enzymatic activity of DRP1 is critical in CS-A cells, suggesting DRP1 as a potential therapeutic target as well as its inhibitors as potential therapeutic tools.

Enzymatic activity of Drp1 link mitochondrial dysfunction to neurodegenerative features in Cockayne Syndrome A cells

Barbara Pascucci;
2019

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 and excessive mitochondrial fission due to hyper-phosphorylation of the mitochondrial fission protein (Drp1)(Pascucci et al.; 2012, 2016). Since we found that pDRP1 and CSA localize at mitochondria after mitochondrial damage, we wondered if DRP1 inhibition was capable to rescue the CSA pathological phenotype. When enzymatic activity of DRP1 is inhibited by MDVI, a mitochondrial fission inhibitor, the high ROS levels are reduced, and the dysfunctional mitochondrial, apoptotic phenotype of CS-A cells is recovered. Moreover, CS-A cells present a significant reduction of nitric oxide (NO) levels respect to WT fibroblasts and interestingly, CS-A cells are characterized by an overexpression of the S-nitrosoglutathione reductase, suggesting for the first time that nitrosative stress might play a role in CS. All these preliminary data clearly indicate that the modulation of enzymatic activity of DRP1 is critical in CS-A cells, suggesting DRP1 as a potential therapeutic target as well as its inhibitors as potential therapeutic tools.
2019
Istituto di Cristallografia - IC
Cockayne syndrome
Oxidative stress
Mitochondrial dysfunction
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14243/368567
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