The role of mitochondrial dysfunction in Cockayne Syndrome

The ERCC8/CSA gene encodes a WD-40 repeat protein that is part of a E3-ubiquitin ligase/COP9 signalosome complex. When mutated it gives rise to a rare recessive progeroid disorder, Cockayne Syndrome group A (CSA), characterized by sun sensitivity and neurodevelopmental abnormalities. CS-A cells are characterized by redox unbalance and mitochondrial dysfunction that may contribute to the neurodegenerative process. In this study we show that CSA localizes to mitochondria and its deficiency leads to accumulation of fragmented mitochondria. The analysis of mitochondrial dynamics showed that in CS-A cells the dynamin-related protein (DRP1) is hyperactivated concomitantly to p53 activation and the mitophagic flux is increased. Efficient rescue of the dysfunctional mitochondrial phenotype and inhibition of apoptotic BCL2-associated X protein (Bax) at mitochondria of CS-A cells was achieved by improving the cell cleaning system via overexpression of Parkin. These findings provide new promising tools for limiting cell loss in CS diseased brain regions.