title: Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction.
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.
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Evandro Fei
authors.initials: EF
authors.lastname: Fang
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Morten
authors.initials: M
authors.lastname: Scheibye-Knudsen
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Lear E
authors.initials: LE
authors.lastname: Brace
authors.affiliation: The Biotechnology Center, University of Oslo, Oslo 0317, Norway.
authors.forename: Henok
authors.initials: H
authors.lastname: Kassahun
authors.affiliation: The Biotechnology Center, University of Oslo, Oslo 0317, Norway.
authors.forename: Tanima
authors.initials: T
authors.lastname: SenGupta
authors.affiliation: The Biotechnology Center, University of Oslo, Oslo 0317, Norway.
authors.forename: Hilde
authors.initials: H
authors.lastname: Nilsen
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Mitchell
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.|Also associated with the Danish Center for Healthy Aging, University of Copenhagen, Copenhagen, Blegdamsvej 3B, 2200, Denmark.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D000375:Aging; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D017173:Caenorhabditis elegans; D002460:Cell Line; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D056564:Sirtuin 1 / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D014983:Xeroderma Pigmentosum / Q000378:metabolism / Q000503:physiopathology*; D051760:Xeroderma Pigmentosum Group A Protein / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases; D056564:Sirtuin 1; D000071246:Uncoupling Protein 2; D051760:Xeroderma Pigmentosum Group A Protein; D000099202:PTEN-Induced Putative Kinase; C447939:SIRT1 protein, human