Overcoming ATM Deficiency by Activating the NAD + /SIRT1 Axis
2016; Cell Press; Volume: 24; Issue: 4 Linguagem: Inglês
10.1016/j.cmet.2016.09.019
ISSN1932-7420
Autores Tópico(s)DNA Repair Mechanisms
ResumoIn this issue, Fang et al., 2016Fang 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. et al.Cell Metab. 2016; 24 (this issue): 566-581PubMed Scopus (325) Google Scholar show that both the DNA repair defect and mitochondrial dysfunction in ATM−/− cells or mice are mitigated by the anti-aging compound nicotinamide riboside or a SIRT1 activator. This broad suppression by activating the NAD+/SIRT1 axis may generally apply to diseases and aging maladies. In this issue, Fang et al., 2016Fang 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. et al.Cell Metab. 2016; 24 (this issue): 566-581PubMed Scopus (325) Google Scholar show that both the DNA repair defect and mitochondrial dysfunction in ATM−/− cells or mice are mitigated by the anti-aging compound nicotinamide riboside or a SIRT1 activator. This broad suppression by activating the NAD+/SIRT1 axis may generally apply to diseases and aging maladies. ATM is a DNA break-triggered kinase that fosters repair along with the Mre11-Rad50-Nbs1 (MRN) complex at the sites of damage (Shiloh and Ziv, 2013Shiloh Y. Ziv Y. Nat. Rev. Mol. Cell Biol. 2013; 14: 197-210Crossref Scopus (1119) Google Scholar). Defects in ATM lead to the disease ataxia telangiectasia (AT), which, in addition to its eponymous symptoms, features uncoordinated movements, cerebellar atrophy, and cancer. Phenotypes of AT are accurately recapitulated in ATM−/− knockout mice. In this issue of Cell Metabolism, Fang et al., 2016Fang 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. et al.Cell Metab. 2016; 24 (this issue): 566-581PubMed Scopus (325) Google Scholar show a broad suppression of phenotypes in ATM−/− mice or atm-1 worms by interventions with small molecules that raise NAD+ levels or activate SIRT1, interventions known to counter effects of normal aging. In previous studies, it was shown that other murine models of diseases caused by defects in DNA repair, such as Xeroderma pigmentosum group A and Cockayne syndrome group B, could also be suppressed by NAD+ repletion by a mechanism requiring SIRT1 (Fang et al., 2014Fang E.F. Scheibye-Knudsen M. Brace L.E. Kassahun H. SenGupta T. Nilsen H. Mitchell J.R. Croteau D.L. Bohr V.A. Cell. 2014; 157: 882-896Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar, Scheibye-Knudsen et al., 2014Scheibye-Knudsen M. Mitchell S.J. Fang E.F. Iyama T. Ward T. Wang J. Dunn C.A. Singh N. Veith S. Hasan-Olive M.M. et al.Cell Metab. 2014; 20: 840-855Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar). Suppression involves another deficit in all of the above diseases and murine models in addition to unrepaired DNA damage: compromised mitochondrial function, which leads to underproduction of ATP and overproduction of reactive oxygen species (ROS). This mitochondrial defect stems from chronically activated poly-ADP-ribose polymerase (PARP) at sites of unrepaired nuclear DNA damage, which depletes the NAD+ substrate used in PARylation of histones and other proteins. Low NAD+ levels then inactivate SIRT1 and other sirtuins, limiting their normal function as custodians of mitochondrial health (Figure 1). These DNA repair studies follow on the heels of earlier ones showing the benefits of NAD+ repletion in promoting healthy metabolic homeostasis in mice (Ramsey et al., 2008Ramsey K.M. Mills K.F. Satoh A. Imai S. Aging Cell. 2008; 7: 78-88Crossref PubMed Scopus (247) Google Scholar, Cantó et al., 2012Cantó C. Houtkooper R.H. Pirinen E. Youn D.Y. Oosterveer M.H. Cen Y. Fernandez-Marcos P.J. Yamamoto H. Andreux P.A. Cettour-Rose P. et al.Cell Metab. 2012; 15: 838-847Abstract Full Text Full Text PDF PubMed Scopus (759) Google Scholar). Fang et al., 2016Fang 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. et al.Cell Metab. 2016; 24 (this issue): 566-581PubMed Scopus (325) Google Scholar present a convincing case for suppression of ATM deficits by the NAD+ precursor nicotinamide riboside (NR), the PARP inhibitor olaparib, or the SIRT1 activator SRT1720 in mammalian neuronal cells and in atm-1 worms. In the case of neuronal cells, these agents reduce apoptosis and PARylation, and restore normal levels of crucial neuronal proteins, BDNF and CREB. In the case of worms, they return healthy mitochondria and normal swimming and pharangeal pumping behavior, and reinstate memory capacity and, indeed, normal lifespan. Suppression in worms requires the SIRT1 ortholog sir-2.1. Microarray, proteomic, and metabolomic data from wild-type, mutant, and suppressed worms reveal details of numerous affected pathways that will be of future value in assessing the range of activities of these interventions. Drilling down on one of these pathways, the authors reveal a failure in mitophagy, the selective targeting of defective mitochondria for degradation, in ATM-depleted HeLa cells. This deficit is neatly suppressed by treatment of cells with NR. In atm-1 worms, a similar breakdown is observed in a mitophagy pathway driven by DCT-1 (homolog of mammalian NIX/BPIP3L), PINK-1, and PDR-1, which is also suppressed by NR. Both sir-2.1 and daf-16 are required for the actual expression of DCT-1, and thus for suppression of mitochondrial defects in worms. Perhaps most surprisingly, the DNA repair phenotype itself is also suppressed by NAD precursors NR or NMN (nicotinamide mononucleotide) (Figure 1). For example, in HeLa cells, ATM depletion leads to a measurable reduction in the efficiency of non-homologous end joining, and this deficit is suppressed by NR. Suppression is partly abolished by knockdown of SIRT1 and fully abolished by knockdown of both SIRT1 and SIRT6, the two sirtuins previously implicated in DNA repair (Chalkiadaki and Guarente, 2015Chalkiadaki A. Guarente L. Nat. Rev. Cancer. 2015; 15: 608-624Crossref PubMed Scopus (322) Google Scholar). The mechanism of suppression may relate to restored deacetylation of Ku70 by SIRT1 and increased phosphorylation of DNA-dependent protein kinase (DNAPK). In atm-1 worms, DNA damage leads to a decrease in brood size and an increase in males (due to increased non-disjunction of the X chromosome during meiosis), which are both suppressed by NR. As a grand finale, the authors examine the effects on ATM−/− mice of NR or NMN supplied in the drinking water. They report a striking suppression of deleterious phenotypes, including motor and memory deficits, a decrease in the number of Purkinje cells in the cerebellum, increased PARylation and defective mitochondria in the cerebellum, thymic hypertrophy, and shortened survival. In the last instance, ATM−/− mice show a mean survival of about 100 days and a maximum survival of 150 days. In contrast, in the NR-treated ATM−/− cohort, 80% were still alive at 300 days, the endpoint of the study. It will be important to repeat this potentially stunning extension of survival with larger cohorts and for longer durations. The observed suppression of phenotypes in ATM−/− animals begs the question of whether NAD+ is depleted in AT, and, if so, whether NAD+ repletion would be an effective therapeutic strategy for this devastating disease. More generally, it is possible that NAD+ is depleted in other unhealthy conditions and a target for NAD+ repletion therapy. These might include other diseases that affect the health of neurons, such as ALS, Alzheimer’s, and Parkinson’s disease. It is also possible that treatment might improve conditions that can be induced by lifestyle issues. One example is diabetes, which is associated with a reduction in SIRT1 activity and can be ameliorated by NR in mice fed the high-fat diet (Cantó et al., 2012Cantó C. Houtkooper R.H. Pirinen E. Youn D.Y. Oosterveer M.H. Cen Y. Fernandez-Marcos P.J. Yamamoto H. Andreux P.A. Cettour-Rose P. et al.Cell Metab. 2012; 15: 838-847Abstract Full Text Full Text PDF PubMed Scopus (759) Google Scholar). More speculatively, liver damage caused by alcoholism might be partly due to NAD+ depletion by chronic and excessive induction of liver alcohol dehydrogenase, which uses NAD+ as a co-factor. By analogy, non-alcoholic fatty liver disease has already been shown to respond favorably to NR treatment in mice (Zhou et al., 2016Zhou C.C. Yang X. Hua X. Liu J. Fan M.B. Li G.Q. Song J. Xu T.Y. Li Z.Y. Guan Y.F. et al.Br. J. Pharmacol. 2016; 173: 2352-2368Crossref PubMed Scopus (115) Google Scholar). Finally, it is notable that the syndromes due to DNA repair deficits show considerable overlap with normal aging. While this coincidence has traditionally been ascribed to effects of accumulated DNA damage and apoptosis on tissue integrity, it seems likely that the indirect effects of DNA damage on the quality of mitochondria help drive the aging phenotypes. In normal aging, additional deterioration, such as oxidative damage to cellular constituents, probably contributes to mitochondrial decline. It is noteworthy that mitochondrial dysfunction as a result of normal aging can be ameliorated by NAD+ repletion in mice (Gomes et al., 2013Gomes A.P. Price N.L. Ling A.J. Moslehi J.J. Montgomery M.K. Rajman L. White J.P. Teodoro J.S. Wrann C.D. Hubbard B.P. et al.Cell. 2013; 155: 1624-1638Abstract Full Text Full Text PDF PubMed Scopus (919) Google Scholar). If NAD+ were to function similarly in humans, it would close the circle on the NAD+/sirtuin pathway, which was first linked to replicative aging in budding yeast (Kennedy et al., 1995Kennedy B.K. Austriaco Jr., N.R. Zhang J. Guarente L. Cell. 1995; 80: 485-496Abstract Full Text PDF PubMed Scopus (409) Google Scholar). L.G. is a founder of Elysium Health and a consultant for GSK. NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA RepairFang et al.Cell MetabolismOctober 11, 2016In BriefMitochondrial damage and NAD+ depletion are key features in ataxia telangiectasia. Fang et al. show that mitochondrial dysfunction in ATM deficiency is caused by compromised mitophagy due to NAD+/SIRT1 inhibition. NAD+ replenishment significantly extends lifespan and improves healthspan in both ATM− worms and mice through mitophagy and DNA repair. Full-Text PDF Open Archive
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