Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction

Cell. 2014 May 8;157(4):882-896. doi: 10.1016/j.cell.2014.03.026.


Mitochondrial dysfunction is a common feature in neurodegeneration and aging. We identify mitochondrial dysfunction in xeroderma pigmentosum group A (XPA), a nucleotide excision DNA repair disorder with severe neurodegeneration, in silico and in vivo. XPA-deficient cells show defective mitophagy with excessive cleavage of PINK1 and increased mitochondrial membrane potential. The mitochondrial abnormalities appear to be caused by decreased activation of the NAD(+)-SIRT1-PGC-1α axis triggered by hyperactivation of the DNA damage sensor PARP-1. This phenotype is rescued by PARP-1 inhibition or by supplementation with NAD(+) precursors that also rescue the lifespan defect in xpa-1 nematodes. Importantly, this pathogenesis appears common to ataxia-telangiectasia and Cockayne syndrome, two other DNA repair disorders with neurodegeneration, but absent in XPC, a DNA repair disorder without neurodegeneration. Our findings reveal a nuclear-mitochondrial crosstalk that is critical for the maintenance of mitochondrial health.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging
  • Animals
  • Apoptosis
  • Autophagy
  • Caenorhabditis elegans
  • Cell Line
  • Humans
  • Ion Channels / metabolism
  • Mice
  • Mitochondrial Proteins / metabolism
  • Mitophagy*
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Protein Kinases / metabolism
  • Rats
  • Sirtuin 1 / metabolism*
  • Uncoupling Protein 2
  • Xeroderma Pigmentosum / metabolism
  • Xeroderma Pigmentosum / physiopathology*
  • Xeroderma Pigmentosum Group A Protein / metabolism*


  • Ion Channels
  • Mitochondrial Proteins
  • Uncoupling Protein 2
  • Xeroderma Pigmentosum Group A Protein
  • Poly(ADP-ribose) Polymerases
  • Protein Kinases
  • PTEN-induced putative kinase
  • SIRT1 protein, human
  • Sirtuin 1

Associated data

  • GEO/GSE55486