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.
N1 - Funding Information:
We thank Boris M. Brenerman, Lynn Froetscher, and Dr. Yujun Hou for their help in the experiments. We appreciate Drs. Kevin Becker; Yongqing Zhang; William H. Wood, III; and Elin Lehrmann for their help in performing microarray and data analysis. We acknowledge Drs. Monica Driscoll, Johan Auwerx, David H. Hall, Coleen T. Murphy, Malene Hansen, Ann M. Rose, and Nektarios Tavernarakis for their expertise in the C. elegans studies. We thank Ståle Nygård for statistical support and Bernd Thiede for access to the University of Oslo Mass Spectrometry Core facility. We thank Drs. Atsushi Miyawaki and Richard J. Youle for sharing mt-mKeima plasmid and mt-mKeima integrated Hela cells, and Drs. Nuo Sun and Toren Finkel for their expertise on mt-mKeima-related imaging. We thank Drs. Yie Liu and Beverly Baptiste for critical reading of the manuscript. This research was supported by the Intramural Research Program of the NIH (V.A.B.), the National Institute on Ageing, a 2014–2015 NIA intra-laboratory grant (E.F.F. and V.A.B.), ChromaDex (V.A.B.), a grant from the South East Norway Regional Health Authority (no. 2015029) (H.N.), the Norwegian Cancer Society grant no. 4514636 (R.C.B.), NIH/NIA grant 5R37AG028730-09, and support from the Glenn Medical Foundation (D.A.S.). The V.A.B. laboratory has CRADA arrangements with ChromaDex and GlaxoSmithKline. D.A.S. is a consultant for GSK, Ovascience, and Metrobiotech.
Publisher Copyright:
© 2016
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 -