Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders

Autophagy. 2014 Aug;10(8):1468-9. doi: 10.4161/auto.29321. Epub 2014 Jun 12.


DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD(+) (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging.

Keywords: DNA repair; SIRT1; autophagy; mitophagy; xeroderma pigmentosum group A.

MeSH terms

  • Animals
  • DNA Damage
  • DNA Repair*
  • Humans
  • Ion Channels / metabolism
  • Membrane Potential, Mitochondrial
  • Mitochondrial Proteins / metabolism
  • Mitophagy*
  • Models, Biological
  • Nerve Degeneration / pathology*
  • Transcription Factors / metabolism
  • Uncoupling Protein 1


  • Ion Channels
  • Mitochondrial Proteins
  • Transcription Factors
  • Uncoupling Protein 1