NAD(+) Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair

Evandro Fei Fang; Henok Kassahun; Deborah L Croteau; Morten Scheibye-Knudsen; Krisztina Marosi; Huiming Lu; Raghavendra A Shamanna; Sumana Kalyanasundaram; Ravi Chand Bollineni; Mark A Wilson; Wendy B Iser; Bradley N Wollman; Marya Morevati; Jun Li; Jesse S Kerr; Qiping Lu; Tyler B Waltz; Jane Tian; David A Sinclair; Mark P Mattson; Hilde Nilsen; Vilhelm A Bohr

doi:10.1016/j.cmet.2016.09.004

NAD(+) Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair

Evandro Fei Fang, Henok Kassahun, Deborah L Croteau, Morten Scheibye-Knudsen, Krisztina Marosi, Huiming Lu, Raghavendra A Shamanna, Sumana Kalyanasundaram, Ravi Chand Bollineni, Mark A Wilson, Wendy B Iser, Bradley N Wollman, Marya Morevati, Jun Li, Jesse S Kerr, Qiping Lu, Tyler B Waltz, Jane Tian, David A Sinclair, Mark P MattsonHilde Nilsen, Vilhelm A Bohr

198 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Cell Metabolism
Vol/bind	24
Udgave nummer	4
Sider (fra-til)	566-581
Antal sider	16
ISSN	1550-4131
DOI	https://doi.org/10.1016/j.cmet.2016.09.004
Status	Udgivet - 11 okt. 2016

Adgang til dokumentet

10.1016/j.cmet.2016.09.004

http://www.cell.com/article/S155041311630482X/pdf

Citationsformater

Fang, E. F., Kassahun, H., Croteau, D. L., Scheibye-Knudsen, M., Marosi, K., Lu, H., Shamanna, R. A., Kalyanasundaram, S., Bollineni, R. C., Wilson, M. A., Iser, W. B., Wollman, B. N., Morevati, M., Li, J., Kerr, J. S., Lu, Q., Waltz, T. B., Tian, J., Sinclair, D. A., ... Bohr, V. A. (2016). NAD(+) Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair. Cell Metabolism, 24(4), 566-581. https://doi.org/10.1016/j.cmet.2016.09.004

Fang, EF, Kassahun, H, Croteau, DL, Scheibye-Knudsen, M, Marosi, K, Lu, H, Shamanna, RA, Kalyanasundaram, S, Bollineni, RC, Wilson, MA, Iser, WB, Wollman, BN, Morevati, M, Li, J, Kerr, JS, Lu, Q, Waltz, TB, Tian, J, Sinclair, DA, Mattson, MP, Nilsen, H & Bohr, VA 2016, 'NAD(+) Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair', Cell Metabolism, bind 24, nr. 4, s. 566-581. https://doi.org/10.1016/j.cmet.2016.09.004

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title = "NAD(+) Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair",

abstract = "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.",

author = "Fang, {Evandro Fei} and Henok Kassahun and Croteau, {Deborah L} and Morten Scheibye-Knudsen and Krisztina Marosi and Huiming Lu and Shamanna, {Raghavendra A} and Sumana Kalyanasundaram and Bollineni, {Ravi Chand} and Wilson, {Mark A} and Iser, {Wendy B} and Wollman, {Bradley N} and Marya Morevati and Jun Li and Kerr, {Jesse S} and Qiping Lu and Waltz, {Tyler B} and Jane Tian and Sinclair, {David A} and Mattson, {Mark P} and Hilde Nilsen and Bohr, {Vilhelm A}",

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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 - Published by Elsevier Inc.

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.

U2 - 10.1016/j.cmet.2016.09.004

DO - 10.1016/j.cmet.2016.09.004

M3 - Journal article

C2 - 27732836

SN - 1550-4131

VL - 24

SP - 566

EP - 581

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

NAD(+) Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair

Abstract

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