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miR-34a and the Cardiomyopathy of Senescence: SALT PNUTS, SALT PNUTS!

2013; Cell Press; Volume: 17; Issue: 5 Linguagem: Inglês

10.1016/j.cmet.2013.04.004

1932-7420

Gerald W. Dorn,

Adipose Tissue and Metabolism

The search for eternal youth is age old. In a recent Nature paper, Boon et al., 2013Boon R.A. Iekushi K. Lechner S. Seeger T. Fischer A. Heydt S. Kaluza D. Tréguer K. Carmona G. Bonauer A. et al.Nature. 2013; 495: 107-110Crossref PubMed Scopus (602) Google Scholar describe DNA damage mechanisms and cardiac senescence provoked by miR-34a and its target, PNUTS. Interrupting this pathway may prevent age- and stress-induced cardiac degeneration. The search for eternal youth is age old. In a recent Nature paper, Boon et al., 2013Boon R.A. Iekushi K. Lechner S. Seeger T. Fischer A. Heydt S. Kaluza D. Tréguer K. Carmona G. Bonauer A. et al.Nature. 2013; 495: 107-110Crossref PubMed Scopus (602) Google Scholar describe DNA damage mechanisms and cardiac senescence provoked by miR-34a and its target, PNUTS. Interrupting this pathway may prevent age- and stress-induced cardiac degeneration. “Middle age ends and senescence begins, the day your descendants outnumber your friends.”(Ogden Nash)“It’s not the years, honey, it's the mileage.”(Indiana Jones, Raiders of the Lost Ark, 1981) If we are fortunate, we will all get old. But there are striking interindividual differences in the aging phenotype, and the consequences of aging on different organ systems within a given individual are inconsistent. Senescence is therefore variable and potentially modifiable. Caloric restriction extends lifespan and diminishes age-related functional decline via activation of sirtuin family (SIRT) NAD-dependent deacetylases (Lin et al., 2000Lin S.J. Defossez P.A. Guarente L. Science. 2000; 289: 2126-2128Crossref PubMed Scopus (1478) Google Scholar). The possibility that master regulatory factors such as SIRTs determine aging phenotypes is attractive because it suggests gene-based interventions to prevent or delay senescence. The ability of microRNAs (miRNAs) to directly modulate messenger RNA (mRNA) stability and protein translation, and to indirectly regulate gene transcription and posttranslational protein modification within a common biological pathway (Hu et al., 2012Hu Y. Matkovich S.J. Hecker P.A. Zhang Y. Edwards J.R. Dorn 2nd, G.W. Proc. Natl. Acad. Sci. USA. 2012; 109: 19864-19869Crossref PubMed Scopus (56) Google Scholar), makes them attractive candidate orchestrators of programmed senescence or anti-aging/reparative processes. Recently, Boon et al., 2013Boon R.A. Iekushi K. Lechner S. Seeger T. Fischer A. Heydt S. Kaluza D. Tréguer K. Carmona G. Bonauer A. et al.Nature. 2013; 495: 107-110Crossref PubMed Scopus (602) Google Scholar identified miR-34a as a central factor provoking cell deterioration in the aging or infarcted heart. miR-34a is a ubiquitously expressed microRNA transcriptionally regulated by a tumor suppressor gene, p53 (Chang et al., 2007Chang T.C. Wentzel E.A. Kent O.A. Ramachandran K. Mullendore M. Lee K.H. Feldmann G. Yamakuchi M. Ferlito M. Lowenstein C.J. et al.Mol. Cell. 2007; 26: 745-752Abstract Full Text Full Text PDF PubMed Scopus (1716) Google Scholar), that encodes a transcription factor tasked with coordinating cellular responses to DNA damage (Figure 1). To fully appreciate the implications of miR-34a on cardiac senescence, it is helpful to understand the interactions between DNA damage, induction of p53, and regulation of miR-34a. Modest DNA damage induces low levels of p53 that activate endogenous DNA repair pathways and promote cell rejuvenation, whereas severe DNA damage that is beyond repair induces high levels of p53 that eliminate the cell via apoptosis (Figure 1). Cell senescence is induced by intermediate levels of DNA damage and p53 activation that induce cell-cycle arrest at the G2-M DNA damage checkpoint, permitting extensive DNA repair. Permanent cell-cycle arrest at this DNA damage checkpoint defines cellular senescence (Collado et al., 2007Collado M. Blasco M.A. Serrano M. Cell. 2007; 130: 223-233Abstract Full Text Full Text PDF PubMed Scopus (1262) Google Scholar). The critical effectors linking DNA damage, p53, and miR-34a signaling (Figure 1) were discovered in several cancers (Chang et al., 2007Chang T.C. Wentzel E.A. Kent O.A. Ramachandran K. Mullendore M. Lee K.H. Feldmann G. Yamakuchi M. Ferlito M. Lowenstein C.J. et al.Mol. Cell. 2007; 26: 745-752Abstract Full Text Full Text PDF PubMed Scopus (1716) Google Scholar), and important regulatory roles were described for the anti-aging protein sirtuin 1 (SIRT1) (Figure 1) and epigenetic miR-34a suppression via methylation of its promoter (Figure 1). Whereas cancer is associated with decreased miR-34a, its levels increase with senescence in normal hearts and spleens, contributing to age-related decreases in SIRT1 levels (Ito et al., 2010Ito T. Yagi S. Yamakuchi M. Biochem. Biophys. Res. Commun. 2010; 398: 735-740Crossref PubMed Scopus (282) Google Scholar). In a recent paper published in Nature, Boon et al., 2013Boon R.A. Iekushi K. Lechner S. Seeger T. Fischer A. Heydt S. Kaluza D. Tréguer K. Carmona G. Bonauer A. et al.Nature. 2013; 495: 107-110Crossref PubMed Scopus (602) Google Scholar identified a novel pathway by which age-related increases in miR-34a contribute to cardiac senescence via a mechanism that seems independent of SIRT1. Parallels are described between miR-34a mediation of functional cardiac deterioration with age and after myocardial infarction (MI). Thus, cardiac miR-34a levels approximately doubled with age in mouse and human hearts and increased in MI border zones. Therapeutically, miR-34a gene ablation or miR-34a suppression by locked nucleic acid-based antimiRs improved left ventricular ejection performance, diminished cardiomyocyte apoptosis, and improved ventricular remodeling in age-induced cardiac senescence (∼18-month-old mice), a genetic model of accelerated aging (Ku80 knockout mice) and post-MI. The central factor in this schema is the phosphatase-1 nuclear targeting subunit (PNUTS), identified as a novel miR-34a target using bioinformatics analyses and validated using luciferase reporter assays. Age- or MI-related increases in miR-34a decreased PNUTS levels. Consequently, forced PNUTS expression reduced age- and miR-34a-related markers of DNA damage and protected cardiomyocytes from apoptosis by preventing telomere shortening (a marker of senescence) and promoting other aspects of the DNA damage response. These findings reveal a novel, SIRT1-independent arm of miR-34a signaling (Figure 1). PNUTS is a catalytically inactive nuclear-localized protein whose titular function is to complex with protein phosphatase-1 (PP1), targeting it to nuclear DNA during mitosis telophase and promoting PP1-mediated chromosome decondensation necessary for interphase. Because PP1 reverses cyclin-dependent kinase-mediated phosphorylation of the retinoblastoma protein (Rb), dissociation of PNUTS from PP1 provoked by cellular stress can regulate cell proliferation and apoptosis (De Leon et al., 2008De Leon G. Sherry T.C. Krucher N.A. Cancer Biol. Ther. 2008; 7: 833-841Crossref PubMed Scopus (37) Google Scholar) (Figure 1). PNUTS also has multiple PP1-independent functions in cell growth and DNA damage response pathways: PNUTS positively regulates cytoprotective PI3K/Akt signaling through nuclear sequestration of another phosphatase, PTEN, which converts Akt-activating PIP3 to inactive PIP2 (Kavela et al., 2013Kavela S. Shinde S.R. Ratheesh R. Viswakalyan K. Bashyam M.D. Gowrishankar S. Vamsy M. Pattnaik S. Rao S. Sastry R.A. et al.Cancer Res. 2013; 73: 205-214Crossref PubMed Scopus (40) Google Scholar) (Figure 1). PNUTS interacts with telomere repeat factor 2 (TRF2) (Kim et al., 2009Kim H. Lee O.H. Xin H. Chen L.Y. Qin J. Chae H.K. Lin S.Y. Safari A. Liu D. Songyang Z. Nat. Struct. Mol. Biol. 2009; 16: 372-379Crossref PubMed Scopus (103) Google Scholar), which protects chromosome ends by enforcing a T-loop structure. DNA damage promotes PNUTS translocation to, and repair of, double-stranded DNA breaks during the G2-M checkpoint (Landsverk et al., 2010Landsverk H.B. Mora-Bermúdez F. Landsverk O.J. Hasvold G. Naderi S. Bakke O. Ellenberg J. Collas P. Syljuåsen R.G. Küntziger T. EMBO Rep. 2010; 11: 868-875Crossref PubMed Scopus (50) Google Scholar) (Figure 1). As a consequence of these parallel effects on multiple targets, modest PNUTS suppression with RNA interference (RNAi), and perhaps by increased miR-34a, prolongs the normal DNA damage checkpoint and delays DNA repair in injured cells (i.e., promotes cell senescence) (Landsverk et al., 2010Landsverk H.B. Mora-Bermúdez F. Landsverk O.J. Hasvold G. Naderi S. Bakke O. Ellenberg J. Collas P. Syljuåsen R.G. Küntziger T. EMBO Rep. 2010; 11: 868-875Crossref PubMed Scopus (50) Google Scholar), thus provoking p53-independent apoptosis (De Leon et al., 2008De Leon G. Sherry T.C. Krucher N.A. Cancer Biol. Ther. 2008; 7: 833-841Crossref PubMed Scopus (37) Google Scholar). Boon et al., 2013Boon R.A. Iekushi K. Lechner S. Seeger T. Fischer A. Heydt S. Kaluza D. Tréguer K. Carmona G. Bonauer A. et al.Nature. 2013; 495: 107-110Crossref PubMed Scopus (602) Google Scholar have extended these findings and provided insight into how epitranscriptional programming of aging and injured hearts directs genetically programmed senescence. The advantages of limiting DNA damage that accumulates with aging or is induced by injury are obvious. Mended cells can re-enter the cell cycle, while cells that are beyond repair are apoptotically culled or placed in permanent cell-cycle arrest to contain the damaged genomic contagion. This explains the tumor-suppressive function of miR-34a and p53. The unresolved question is how protective DNA repair and resulting permanent cell-cycle arrest (i.e., cellular senescence [Collado et al., 2007Collado M. Blasco M.A. Serrano M. Cell. 2007; 130: 223-233Abstract Full Text Full Text PDF PubMed Scopus (1262) Google Scholar]) impacts the heart, since cardiac myocytes are essentially amitotic. An intriguing possibility is that the miR-34a/PNUTS axis is active not only in aging and injured cardiac myocytes, but also in the resident cardiomyocyte progenitor cells that are essential for myocardial maintenance and renewal. Cardiac stem cells decline with age, and miR-34a/PNUTS-mediated progenitor cell depletion and/or proliferative arrest would further impair the intrinsic regenerative capacity of the heart by destroying its reservoir of cardiomyocyte-producing cells, leading to the net loss of myocardium and functional cardiac insufficiency that is seen with aging and late post-MI. Whether and how stem cell depletion by miR-34a contributes to cardiac senescence requires further evaluation. The author acknowledges Dizzy Gillespie and Charlie Parker for inspiring the title.