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Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome
Edited by Philip C. Hanawalt, Stanford University, Stanford, CA, and approved April 14, 2015 (received for review November 20, 2014)

Significance
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.
Abstract
UV-sensitive syndrome (UVSS) and Cockayne syndrome (CS) are human disorders caused by CSA or CSB gene mutations; both conditions cause defective transcription-coupled repair and photosensitivity. Patients with CS also display neurological and developmental abnormalities and dramatic premature aging, and their cells are hypersensitive to oxidative stress. We report CSA/CSB-dependent depletion of the mitochondrial DNA polymerase-γ catalytic subunit (POLG1), due to HTRA3 serine protease accumulation in CS, but not in UVsS or control fibroblasts. Inhibition of serine proteases restored physiological POLG1 levels in either CS fibroblasts and in CSB-silenced cells. Moreover, patient-derived CS cells displayed greater nitroso-redox imbalance than UVSS cells. Scavengers of reactive oxygen species and peroxynitrite normalized HTRA3 and POLG1 levels in CS cells, and notably, increased mitochondrial oxidative phosphorylation, which was altered in CS cells. These data reveal critical deregulation of proteases potentially linked to progeroid phenotypes in CS, and our results suggest rescue strategies as a therapeutic option.
Footnotes
↵1Present address: Stem Cells & Development, Department of Developmental and Stem Cell Biology, Institut Pasteur, 75724 Paris, France.
- ↵2To whom correspondence should be addressed. Email: mricch{at}pasteur.fr.
Author contributions: L.C., D.S.F.B., A.S., and M.R. designed research; L.C. and D.S.F.B. performed research; D.S.F.B. contributed new reagents/analytic tools; L.C., D.S.F.B., A.S., and M.R. analyzed data; and L.C., A.S., and M.R. wrote the paper.
Conflict of interest statement: A European Patent application (EP 14 305 203), based on the findings of the present manuscript, has been submitted for the therapeutic methods against progeroid-like syndromes or symptoms.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1422264112/-/DCSupplemental.
Freely available online through the PNAS open access option.