The mechanisms governing ageing, which is a multifactorial process, have not been resolved and constitute a fundamental open question in cell and organismal biology. Ageing is dramatically accelerated in some rare genetic disorders. Dissecting the defect(s) of these diseases is critical to develop treatments and elucidate dysfunctions that might lead to normal ageing. The Cockayne syndrome (CS) is characterized by photosensitivity, severe neurodevelopmental defects, and dramatically precocious ageing.
By assessing patient-derived primary cells we showed that CS alterations are rather linked to impairment of the mitochondrial DNA replication complex, in particular depletion of the catalytic mitochondrial DNA polymerase. This alteration affects mitochondrial ATP production, and is due to accumulation of the HTRA3 serine protease. HTRA3 is in turn overexpressed by increased nitroso-oxidative stress. We rescued mitochondrial alterations in CS patient cells with drugs that act on serine proteases or scavenge reactive oxygen and nitrogen species, opening novel possibilities for treatments, which are presently lacking for CS patients.
We investigate genetic and epigenetic mechanism(s) by which CSA/B impairment promotes HTRA3 overexpression, the extent of mitochondrial and cellular protein depletion upon HTRA3 overexpression, and the occurrence of these events during normal ageing.