TY - JOUR
T1 - NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair
AU - Fang, Evandro Fei
AU - Kassahun, Henok
AU - Croteau, Deborah L.
AU - Scheibye-Knudsen, Morten
AU - Marosi, Krisztina
AU - Lu, Huiming
AU - Shamanna, Raghavendra A.
AU - Kalyanasundaram, Sumana
AU - Bollineni, Ravi Chand
AU - Wilson, Mark A.
AU - Iser, Wendy B.
AU - Wollman, Bradley N.
AU - Morevati, Marya
AU - Li, Jun
AU - Kerr, Jesse S.
AU - Lu, Qiping
AU - Waltz, Tyler B.
AU - Tian, Jane
AU - Sinclair, David A.
AU - Mattson, Mark P.
AU - Nilsen, Hilde
AU - Bohr, Vilhelm A.
PY - 2016/10/11
Y1 - 2016/10/11
N2 - Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD+, and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD+ reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD+ also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions.
AB - Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD+, and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD+ reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD+ also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions.
UR - http://www.scopus.com/inward/record.url?scp=84992343671&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84992343671&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2016.09.004
DO - 10.1016/j.cmet.2016.09.004
M3 - Article
C2 - 27732836
AN - SCOPUS:84992343671
SN - 1550-4131
VL - 24
SP - 566
EP - 581
JO - Cell Metabolism
JF - Cell Metabolism
IS - 4
ER -