Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction
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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.
|Number of pages||15|
|Publication status||Published - 8 May 2014|
- Aging, Animals, Apoptosis, Autophagy, Caenorhabditis elegans, Cell Line, Humans, Ion Channels, Mice, Mitochondrial Degradation, Mitochondrial Proteins, Poly(ADP-ribose) Polymerases, Protein Kinases, Rats, Sirtuin 1, Xeroderma Pigmentosum, Xeroderma Pigmentosum Group A Protein