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

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

来源：Cell Metabolism, 2016, 24(4): 566-581.

DOI：10.1016/j.cmet.2016.09.004

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.

• 出版日期2016-10-11