title: Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders.
abstract: DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD(+) (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging.
authors.affiliation: Laboratory of Molecular Gerontology; National Institute on Aging; National Institutes of Health; Baltimore, MD USA.
authors.forename: Morten
authors.initials: M
authors.lastname: Scheibye-Knudsen
authors.affiliation: Laboratory of Molecular Gerontology; National Institute on Aging; National Institutes of Health; Baltimore, MD 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 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 USA.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D000818:Animals; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy; D008954:Models, Biological; D009410:Nerve Degeneration / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D014157:Transcription Factors; D000071256:Uncoupling Protein 1
keywords: DNA repair; SIRT1; autophagy; mitophagy; xeroderma pigmentosum group A