Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome

Ageing is dramatically accelerated in Cockayne syndrome (CS), but the impairments that lead to this phenotype have not been elucidated. The DNA repair proteins CSA or CSB are mutated in CS, but premature ageing is not caused by the DNA repair defect. CSB also affects mitochondrial turnover. Our data reveal a novel pathway that is affected in CS cells. We show that CSB deregulates the expression of a serine protease, which degrades mitochondrial DNA polymerase gamma and impairs mitochondrial function. We rescue this defect, by two independent strategies, in primary cells from patients. Our findings open novel possibilities for developing treatments, which are presently missing for CS patients. Abnormalities revealed here might occur at a slower rate during normal physiological ageing.