Research Papers:

Overexpression of parkin rescues the defective mitochondrial phenotype and the increased apoptosis of Cockayne Syndrome A cells

Barbara Pascucci, Mariarosaria D’Errico, Alessandra Romagnoli, Chiara De Nuccio, Miriam Savino, Donatella Pietraforte, Manuela Lanzafame, Angelo Salvatore Calcagnile, Paola Fortini, Sara Baccarini, Donata Orioli, Paolo Degan, Sergio Visentin, Miria Stefanini, Ciro Isidoro, Gian Maria Fimia and Eugenia Dogliotti _

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Oncotarget. 2017; 8:102852-102867. https://doi.org/10.18632/oncotarget.9913

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Barbara Pascucci1,2,*, Mariarosaria D’Errico2,*, Alessandra Romagnoli3, Chiara De Nuccio4, Miriam Savino5, Donatella Pietraforte4, Manuela Lanzafame6, Angelo Salvatore Calcagnile2, Paola Fortini2, Sara Baccarini2, Donata Orioli6, Paolo Degan7, Sergio Visentin4, Miria Stefanini6, Ciro Isidoro5, Gian Maria Fimia3,8 and Eugenia Dogliotti2

1 Institute of Crystallography, Consiglio Nazionale delle Ricerche, Monterotondo Stazione, Rome, Italy

2 Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena, Rome, Italy

3 Department Epidemiology and Preclinical Research, INMI L. Spallanzani IRCCS, Rome, Italy

4 Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena, Rome, Italy

5 Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy

6 Institute of Molecular Genetics, Consiglio Nazionale delle Ricerche, Pavia, Italy

7 IRCCS Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genova, Italy

8 Department of Biological and Environmental Sciences and Technologies (DiSTeBA), Università del Salento, Lecce, Italy

* Co-first author

Correspondence to:

Mariarosaria D’Errico, email:

Eugenia Dogliotti, email:

Keywords: cockayne syndrome, mitochondrial dysfunction, ROS, mitophagy

Received: May 17, 2016 Accepted: May 26, 2016 Published: June 07, 2016


The ERCC8/CSA gene encodes a WD-40 repeat protein (CSA) that is part of a E3-ubiquitin ligase/COP9 signalosome complex. When mutated, CSA causes the Cockayne Syndrome group A (CS-A), a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. CS-A cells features include ROS hyperproduction, accumulation of oxidative genome damage, mitochondrial dysfunction and increased apoptosis that may contribute to the neurodegenerative process. In this study, we show that CSA localizes to mitochondria and specifically interacts with the mitochondrial fission protein dynamin-related protein (DRP1) that is hyperactivated when CSA is defective. Increased fission is not counterbalanced by increased mitophagy in CS-A cells thus leading to accumulation of fragmented mitochondria. However, when mitochondria are challenged with the mitochondrial toxin carbonyl cyanide m-chloro phenyl hydrazine, CS-A fibroblasts undergo mitophagy as efficiently as normal fibroblasts, suggesting that this process remains targetable to get rid of damaged mitochondria. Indeed, when basal mitophagy was potentiated by overexpressing Parkin in CSA deficient cells, a significant rescue of the dysfunctional mitochondrial phenotype was observed. Importantly, Parkin overexpression not only reactivates basal mitophagy, but plays also an anti-apoptotic role by significantly reducing the translocation of Bax at mitochondria in CS-A cells. These findings provide new mechanistic insights into the role of CSA in mitochondrial maintenance and might open new perspectives for therapeutic approaches.

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