Abstract
Cockayne syndrome group A (CS-A) is a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. Cells derived from CS-A patients present as pathological hallmarks excessive oxidative stress, mitochondrial fragmentation and apoptosis associated with hyperactivation of the mitochondrial fission dynamin related protein 1 (DRP1). In this study, by using human cell models we further investigated the interplay between DRP1 and CSA and we determined whether pharmacological or genetic inhibition of DRP1 affects disease progression. Both reactive oxygen and nitrogen species are in excess in CS-A cells and when the mitochondrial translocation of DRP1 is inhibited a reduction of these species is observed together with a recovery of mitochondrial integrity and a significant decrease of apoptosis. This study indicates that the CSA-driven modulation of DRP1 pathway is key to control mitochondrial homeostasis and apoptosis and suggests DRP1 as a potential target in the treatment of CS patients.
Highlights
Cockayne syndrome (CS) is a multi-system disorder with defects in the transcription coupled nucleotide excision repair (TC-NER) involved in the repair of UV damage from the transcribed strand of active genes
By targeting dynamin related protein 1 (DRP1) either by pharmacological or genetic knockdown, we show that there is a causal link between DRP1 hyperactivation and Cockayne syndrome group A (CS-A) cell metabolic derangement and excessive apoptosis
We propose that modulation of DRP1 phosphorylation by CSA, and possibly CSB, is crucial to maintain mitochondrial homeostasis
Summary
Cockayne syndrome (CS) is a multi-system disorder with defects in the transcription coupled nucleotide excision repair (TC-NER) involved in the repair of UV damage from the transcribed strand of active genes. CS is cancer-free and the cardinal clinical features are pre- or post-natal growth failure, progressive neurological dysfunction and premature aging. All these symptoms are difficult to trace back to UV damage repair defects only. When enzymatic activity of DRP1 is inhibited, either by chemical inhibition or gene silencing, the dysfunctional mitochondrial and apoptotic phenotype of CS-A cells are recovered. All these data clearly indicate that the modulation of enzymatic activity of DRP1 by post-translational modifications is critical in CS-A cells, suggesting DRP1 as therapeutic target and its inhibitors as potential therapeutic tools
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