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S-Nitrosylation Drives Cell Senescence and Aging in Mammals By S-nitrosylation drives cell senescence and aging in PNAS PLUS mammals by controlling mitochondrial dynamics and mitophagy Salvatore Rizzaa,1, Simone Cardacib,1, Costanza Montagnaa,c,1, Giuseppina Di Giacomod,2, Daniela De Zioa, Matteo Bordid, Emiliano Maiania, Silvia Campellod,e, Antonella Borrecaf, Annibale A. Pucag,h, Jonathan S. Stamleri,j, Francesco Cecconia,d,k, and Giuseppe Filomenia,d,3 aDanish Cancer Society Research Center, Center for Autophagy, Recycling and Disease, 2100 Copenhagen, Denmark; bDivision of Genetics and Cell Biology, Institute for Research and Health Care San Raffaele (IRCCS) Scientific Institute, 20132 Milan, Italy; cInstitute of Sports Medicine Copenhagen, Bispebjerg Hospital, 2400 Copenhagen, Denmark; dDepartment of Biology, Tor Vergata University, 00133 Rome, Italy; eIRCCS Fondazione Santa Lucia, 00146 Rome, Italy; fInstitute of Cellular Biology and Neuroscience, National Research Council, 00143 Rome, Italy; gCardiovascular Research Unit, IRCCS Multimedica, 20138 Milan, Italy; hDipartimento di Medicina e Chirurgia, University of Salerno, 84084 Fisciano Salerno, Italy; iInstitute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH 44106; jHarrington Discovery Institute, University Hospitals Case Medical Center, Cleveland, OH 44106; and kDepartment of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children’s Hospital, 00146 Rome, Italy Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved March 1, 2018 (received for review January 9, 2018) S-nitrosylation, a prototypic redox-based posttranslational modifi- found in experimental models of aging, supporting the idea that cation, is frequently dysregulated in disease. S-nitrosoglutathione GSNOR preserves cellular function. reductase (GSNOR) regulates protein S-nitrosylation by function- The free radical theory of aging postulates that oxidative ing as a protein denitrosylase. Deficiency of GSNOR results in tu- stress, an inevitable consequence of oxygen consumption, results morigenesis and disrupts cellular homeostasis broadly, including in mitochondrial injury and dysfunction. In fact, damaged mi- metabolic, cardiovascular, and immune function. Here, we demon- tochondria, with altered mitochondrial morphology, represent strate that GSNOR expression decreases in primary cells undergo- markers of senescent cells in aging tissues (21–23). Nitrosative BIOCHEMISTRY ing senescence, as well as in mice and humans during their life stress has also been related to aging and linked to excessive span. In stark contrast, exceptionally long-lived individuals main- S-nitrosylation of components of the mitochondrial respiratory tain GSNOR levels. We also show that GSNOR deficiency promotes complexes (24–26). However, the role of mitochondrial nitro- mitochondrial nitrosative stress, including excessive S-nitrosyla- sative stress in cellular senescence is not well understood. Here, tion of Drp1 and Parkin, thereby impairing mitochondrial dynamics we demonstrate that mammalian aging is regulated by epige- and mitophagy. Our findings implicate GSNOR in mammalian lon- netic down-regulation of GSNOR and by the consequently gevity, suggest a molecular link between protein S-nitrosylation enhanced S-nitrosylation of proteins controlling mitochondrial and mitochondria quality control in aging, and provide a redox- dynamics and mitophagy. This offers a unique perspective on based perspective on aging with direct therapeutic implications. Significance aging | S-nitrosylation | GSNOR | mitochondria | mitophagy The free radical theory of aging remains controversial. Accumu- he oxidative modification of cysteine residues by nitric oxide lation of mitochondrial damage is commonly accepted as an age- T(NO) to form S-nitrosothiols (SNOs) is called S-nitrosylation, related phenomenon associated with the inescapable side effects and provides the large part of ubiquitous NO bioactivity (1, 2). of oxidative metabolism. However, to date, molecular determi- Physiological S-nitrosylation modulates the activity of proteins in nants of this phenomenon have not been identified. Previous ev- –S idence indicates that engineered mice deficient in the denitrosylase all functional classes across phylogeny (3). By contrast, hyper - S nitrosylation has been implicated in a wide range of pathophysiol- -nitrosoglutathione reductase (GSNOR) show features of aging. Here, we show that due to epigenetic events, GSNOR expression ogies, including cell senescence and death (4–6). The steady-state declines with age, ultimately resulting in the accumulation of dam- concentration of protein SNOs (PSNOs) reflects manifold equi- aged mitochondria. By contrast, centenarians maintain high libria between protein and low-molecular-weight SNOs that GSNOR expression. Collectively, these data suggest that GSNOR are regulated by rates of S-nitrosylation and denitrosylation. S may act as a longevity protein countering defects in mitochondrial -nitrosylation is a function of NO synthesis, which is catalyzed by physiology that arise from age-related epigenetic deregulation. NO synthases (NOSs), as well as enzymes termed nitrosylases, which directly introduce NO into proteins (7), while deni- Author contributions: S.R., S. Cardaci, C.M., F.C., and G.F. designed research; S.R., C.M., trosylation is catalyzed by denitrosylases, including the enzyme G.D.G., D.D.Z., M.B., E.M., S. Campello, and A.A.P. performed research; M.B., A.B., S-nitrosoglutathione reductase (GSNOR). Although being for- A.A.P., and J.S.S. contributed new reagents/analytic tools; S.R., S. Cardaci, C.M., M.B., E.M., and G.F. analyzed data; and S.R., S. Cardaci, J.S.S., F.C., and G.F. wrote merly characterized as a class III alcohol dehydrogenase (ADH5) the paper. or glutathione-dependent formaldehyde dehydrogenase (FDH), Conflict of interest statement: J.S.S. has received a commercial research grant from No- GSNOR exhibits its highest catalytic efficiency and specificity for vartis and has ownership interest (including patents) in Adamas and Lifehealth. S-nitrosoglutathione (GSNO) reduction (8, 9). Through trans- This article is a PNAS Direct Submission. nitrosylation, the exchange of an NO moiety between SNOs and Published under the PNAS license. free thiols, GSNO is in equilibrium with cellular PSNOs; therefore, 1S.R., S. Cardaci, and C.M. contributed equally to this work. S GSNOR activity affects the extent of protein -nitrosylation (10). 2Present address: Department of Orthopedics and Traumatology, University Campus Bio- Conditions in which NOSs are pathologically activated result in medico, 00128 Rome, Italy. aberrantly enhanced S-nitrosylation, which is associated with cellular 3To whom correspondence should be addressed. Email: [email protected]. – damage (11 13) and disease, such as neurodegeneration (14). Also, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. −/− phenotypes of mice deficient in GSNOR (Gsnor )(15–20), in 1073/pnas.1722452115/-/DCSupplemental. which protein S-nitrosylation is greatly increased, overlap those www.pnas.org/cgi/doi/10.1073/pnas.1722452115 PNAS Latest Articles | 1of10 Downloaded by guest on September 27, 2021 the mitochondrial free radical theory of aging and may open and selected two different cell types: (i) the actively dividing new therapeutic approaches. mouse embryonic fibroblasts (MEFs), which were used as a model of replicative senescence, and (ii) primary cortical neu- Results rons (PCNs), which are postmitotic (terminally differentiated) GSNOR Expression Decreases During Aging and Cell Senescence. cells, and thus used as a canonical model of aging in vitro. As − − Based on the evidence that Gsnor / mice exhibit a number of also reported previously (27, 28), MEFs and PCNs preferen- – tially expressed two different isoforms of NOS (i.e., NOS2 in phenotypes associated with aging (15 20), we decided to analyze SI Appendix A B the impact of GSNOR deficiency on the nervous system. To this MEFs and NOS1 in PCNs; , Fig. S1 and ) and − − end, we screened neocortical samples in 2-mo-old Gsnor / mice produced NO at detectable levels, which was reverted by in- cubation with the pan-NOS inhibitor L-NG-nitroarginine methyl − − for accumulation of protein aggregates, with these commonly ester (L-NAME) (SI Appendix,Fig.S1C and D). When Gsnor / being accepted as markers of premature neurodegeneration. As A Gsnor−/− MEFs were maintained in culture, they showed senescence- shown in Fig. 1 , brains exhibited marked increases in related features, including an increase in nuclear size (Fig. α – ubiquitin- and -synuclein positive protein aggregates that cor- 1C)andβ-galactosidase activity (Fig. 1D) to an extent compa- related with accelerated declines in motor control coordination rable to that observed in WT MEFs undergoing replicative se- (observed at 2 mo) (Fig. 1B), with this also being a distinctive nescence (i.e., after six or eight passages in culture). Similarly, −− feature of aged brains. To investigate in further detail the β-galactosidase activity, evaluated in Gsnor / PCNsafter6dinvitro, mechanisms linking GSNOR to aging, we moved to cell systems was significantly higher than in WT counterparts and, of note, − − Fig. 1. GSNOR decrease is associated with age and cell senescence. (A) Immunofluorescence analyses of brain cortexes from 2-mo-old WT and Gsnor / (KO) mice incubated with antiubiquitin (Ub, red) and anti–α-synuclein (Syn, green) antibodies. DAPI was used to stain nuclei. Ub spot count
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