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

Abstract

SUMMARY 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 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.

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

“…The UPR mt and mitophagy pathways are also potently induced in worms and in various mammalian tissues by NAD + -boosting compounds, such as nicotinamide riboside (NR), and Olaparib (AZD2281 or AZD) 34–37 . Similarly to dox and mrps-5 RNAi, treatment of GMC101 with NR and AZD induced the MSR (Fig.…”

Expanding perspectives on the significance of mitophagy in cancer

“…As discussed above, hypoxia induces BNIP3, BNIP3L and FUNDC1 to promote mitophagy [93–95,122]. In addition, reduced ATP levels activates AMPK which promotes mitophagy via ULK1 activation and mTOR inhibition [158,159] while Sirt1 and other sirtuins sensitive to both cytosolic and mitochondrial pools of NAD+ promote mitophagy through de-acetylation of Atg5, Atg7 and Atg12 [160], as well as induction of dct-1 , the worm homolog of BNIP3/BNIP3L [161]. …”

“…Recent work has suggested a link between mitophagy and DNA damage sensing and repair mechanisms in the cell [53,161,198–200]. Mitochondrial dysfunction has been noted in cells lacking the ATM kinase, a protein that plays a critical role in DNA damage responses and is inactivated in Ataxia-telangiectasia (AT), a cancer predisposition syndrome in which patients display radio-sensitivity amongst other symptoms [198].…”

PPARγ-Coactivator-1α, Nicotinamide Adenine Dinucleotide and Renal Stress Resistance

“…NAD+ serves as a cofactor for deacetylase enzymes known as sirtuins that have been linked to renoprotection [38–40]. Maneuvers to increase NAD+ can boost mitochondrial function and enhance mitophagy [41]. While these pathways will require further study, the emerging body of work suggests that PGC1α-induced defense of NAD+ levels may be critical for the kidney to resist different classes of stressors.…”