1 Section I. Center for Healthy Aging, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 Molecular Aging Program, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet3 Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.4 Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.5 The Biotechnology Center, University of Oslo, Oslo 0317, Norway.
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.
Cell, 2014, Vol 157, Issue 4, p. 882-96
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