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

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

Author information

1
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
2
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
3
The Biotechnology Center, University of Oslo, Oslo 0317, Norway.
4
Also associated with the Danish Center for Healthy Aging, University of Copenhagen, Copenhagen, Blegdamsvej 3B, 2200, Denmark.
#
Contributed equally

Abstract

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.

PMID:
24813611
PMCID:
PMC4625837
DOI:
10.1016/j.cell.2014.03.026
[Indexed for MEDLINE]
Free PMC Article

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