title: NAD+: The convergence of DNA repair and mitophagy.
abstract: ATM is a 350 kDa serine/threonine kinase best known for its role in DNA repair and multiple cellular homeostasis pathways. Mutation in ATM causes the disease ataxia telangiectasia (A-T) with clinical features including ataxia, severe cerebellar atrophy and Purkinje cell loss. In a cross-species study, using primary rat neurons, the roundworm C. elegans, and a mouse model of A-T, we showed that loss of ATM induces mitochondrial dysfunction and compromised mitophagy due to NAD+insufficiency. Remarkably, NAD+repletion mitigates both the DNA repair defect and mitochondrial dysfunction in ATM-deficient neurons. In C. elegans, NAD+repletion can clear accumulated dysfunctional mitochondria through restoration of compromised mitophagy via upregulation of DCT-1. Thus, NAD+ties together DNA repair and mitophagy in neuroprotection and intimates immediate translational applications for A-T and related neurodegenerative DNA repair-deficient diseases.
authors.affiliation: a Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health , Baltimore , MD , USA.
authors.forename: Evandro F
authors.initials: EF
authors.lastname: Fang
authors.affiliation: a 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; D001260:Ataxia Telangiectasia / Q000378:metabolism / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001343:Autophagy; D017173:Caenorhabditis elegans / Q000378:metabolism; D004260:DNA Repair; D051379:Mice; D063306:Mitophagy; D008954:Models, Biological; D009243:NAD / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D009243:NAD; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; DNA damage; ataxia telangiectasia; autophagy; mitophagy