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Costanza Montagna, Claudia Cirotti, Salvatore Rizza, and Giuseppe Filomeni
Antioxidants and Redox Signaling, ISSN: 15230864, eISSN: 15577716, Pages: 884-905, Published: 20 April 2020 Mary Ann Liebert Inc
SIGNIFICANCE Cysteines have an essential role in redox signaling, transforming an oxidant signal into a biological response. Among reversible cysteine post-translational modifications, S-nitrosylation acts as a redox-switch in several patho-physiological events, such as ischemia-reperfusion, synaptic transmission, cancer, and muscular dysfunctions. Recent Advances: Growing pieces of in vitro and in vivo evidence argue for S-nitrosylation being deeply involved in development and aging, and playing a role in the onset of different pathological states. New findings suggest it being an enzymatically regulated cellular process, with deep impact on mitochondrial structure and function, and in cellular metabolism. In light of this, the recent discovery of the new denitrosylase S-nitrosoCoA reductase takes on even greater importance and opens new perspectives on S-nitrosylation as general mechanism of cellular homeostasis. CRITICAL ISSUES Based on these recent findings, we aim at summarizing and elaborating on the established and emerging crucial roles of S-nitrosylation in mitochondrial metabolism and mitophagy, and provide an overview of the patho-physiological effects induced by its deregulation. FUTURE DIRECTIONS The identification of new S-nitrosylation targets, and the comprehension of the mechanisms through which S-nitrosylation modulates specific classes of proteins, i.e. those impinging on diverse mitochondrial functions, may help better understand the pathophysiology of aging, and propose lines of intervention to slow down or extend the onset of aging-related diseases.
Costanza Montagna, Salvatore Rizza, Claudia Cirotti, Emiliano Maiani, Maurizio Muscaritoli, Antonio Musarò, Maria Teresa Carrí, Elisabetta Ferraro, Francesco Cecconi, and Giuseppe Filomeni
Cell Death and Disease, eISSN: 20414889, Published: 1 May 2019 Springer Science and Business Media LLC
Neuronal nitric oxide synthase (nNOS) plays a crucial role in the maintenance of correct skeletal muscle function due, at least in part, to S-nitrosylation of specific protein targets. Similarly, we recently provided evidence for a muscular phenotype in mice lacking the denitrosylase S-nitrosoglutathione reductase (GSNOR). Here, we demonstrate that nNOS and GSNOR are concomitantly expressed during differentiation of C2C12. They colocalizes at the sarcolemma and co-immunoprecipitate in cells and in myofibers. We also provide evidence that GSNOR expression decreases in mouse models of muscular dystrophies and of muscle atrophy and wasting, i.e., aging and amyotrophic lateral sclerosis, suggesting a more general regulatory role of GSNOR in skeletal muscle homeostasis.
Salvatore Rizza, Simone Cardaci, Costanza Montagna, Giuseppina Di Giacomo, Daniela De Zio, Matteo Bordi, Emiliano Maiani, Silvia Campello, Antonella Borreca, Annibale A. Puca, Jonathan S. Stamler, Francesco Cecconi, and Giuseppe Filomeni
Proceedings of the National Academy of Sciences of the United States of America, ISSN: 00278424, eISSN: 10916490, Volume: 115, Pages: E3388-E3397, Published: 2018 Proceedings of the National Academy of Sciences
S-nitrosylation, a prototypic redox-based posttranslational modification, is frequently dysregulated in disease. S-nitrosoglutathione reductase (GSNOR) regulates protein S-nitrosylation by functioning as a protein denitrosylase. Deficiency of GSNOR results in tumorigenesis and disrupts cellular homeostasis broadly, including metabolic, cardiovascular, and immune function. Here, we demonstrate that GSNOR expression decreases in primary cells undergoing senescence, as well as in mice and humans during their life span. In stark contrast, exceptionally long-lived individuals maintain GSNOR levels. We also show that GSNOR deficiency promotes mitochondrial nitrosative stress, including excessive S-nitrosylation of Drp1 and Parkin, thereby impairing mitochondrial dynamics and mitophagy. Our findings implicate GSNOR in mammalian longevity, suggest a molecular link between protein S-nitrosylation and mitochondria quality control in aging, and provide a redox-based perspective on aging with direct therapeutic implications.
Costanza Montagna, Salvatore Rizza, Emiliano Maiani, Lucia Piredda, Giuseppe Filomeni, and Francesco Cecconi
FEBS Journal, ISSN: 1742464X, eISSN: 17424658, Volume: 283, Pages: 3857-3869, Published: 1 November 2016 Wiley
Autophagy is the main catabolic cellular process through which cells adapt their needs (e.g., growth and proliferation) to environmental availability of nutrients (e.g., amino acid and glucose) and growth factors. The rapid activation of the autophagy response essentially depends on protein post-translational modifications (PTMs), which act as molecular switches triggering signaling cascades. Deregulation of autophagy contributes to pathological conditions, such as cancer and neurodegeneration. Therefore, understanding how PTMs affect the occurrence of autophagy is of the highest importance for clinical applications. Besides phosphorylation and ubiquitylation, which represent the best known examples of PTMs, redox-based modifications are also emerging as contributing to the regulation of intracellular signaling. Of note, S-nitrosylation of cysteine residues is a redox PTM and is the principal mechanism of nitric oxide-based signaling. Results emerging in recent years suggest that NO has a role in modulating autophagy. However, the function of S-nitrosylation in autophagy regulation remains still unveiled. By this review, we describe the upstream events regulating autophagy activation focusing on recently published evidence implying a S-nitrosylation-dependent regulation.
Barbara Benassi, Giuseppe Filomeni, Costanza Montagna, Caterina Merla, Vanni Lopresto, Rosanna Pinto, Carmela Marino, and Claudia Consales
Molecular Neurobiology, ISSN: 08937648, eISSN: 15591182, Pages: 4247-4260, Published: 1 August 2016 Springer Science and Business Media LLC
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss, with an etiopathogenesis involving both genetic and environmental factors. The occupational/residential exposure to the electromagnetic fields has been recently associated with an increased risk of neurodegenerative diseases; it has been thus proposed that the extremely low frequency magnetic field (ELF-MF) may contribute to neurodegenerative etiopathogenesis, as its interaction with biological systems directly impairs redox homeostasis in specific areas of the brain. The molecular mechanisms elicited by ELF-MF, and their potential involvement in PD onset, still remain unclear. To this end, we set up a generator of ELF-MF able to stably and homogeneously reproduce environmental prolonged exposure to ELF-MF (50 Hz, 1 mT). Results obtained indicate that ELF-MF exposure alters cell response of SH-SY5Y cells to MPP+. We demonstrate that ELF-MF does not affect per se survival, shape, and morphology of both proliferating and differentiated SH-SY5Y cells but significantly impairs redox homeostasis and thiol content, triggering an increase in protein carbonylation. As a result, toxicity of MPP+, even at low doses, is highly enhanced in ELF-MF-exposed cells due to a significant increase in ROS levels, potentiation of oxidative damage, and induction of a caspase-dependent apoptosis. Pre-incubation with the thiol antioxidants N-acetyl-l-cysteine and GSH ethyl-ester significantly reduces the extent of oxidative damage and protects cells from death induced by the combined treatment ELF-MF/MPP+. Taken overall, our results demonstrate the redox-based molecular interaction between ELF-MF and PD neurotoxins in vitro, and open a new scenario for defining the synergy of environmental factors in PD onset.
Salvatore Rizza, Costanza Montagna, Simone Cardaci, Emiliano Maiani, Giuseppina Di Giacomo, Virginia Sanchez-Quiles, Blagoy Blagoev, Andrea Rasola, Daniela De Zio, Jonathan S. Stamler, Francesco Cecconi, and Giuseppe Filomeni
Cancer Research, ISSN: 00085472, eISSN: 15387445, Pages: 4170-4182, Published: 15 July 2016 American Association for Cancer Research (AACR)
S-nitrosoglutathione reductase (GSNOR) represents the best-documented denitrosylase implicated in regulating the levels of proteins posttranslationally modified by nitric oxide on cysteine residues by S-nitrosylation. GSNOR controls a diverse array of physiologic functions, including cellular growth and differentiation, inflammation, and metabolism. Chromosomal deletion of GSNOR results in pathologic protein S-nitrosylation that is implicated in human hepatocellular carcinoma (HCC). Here we identify a metabolic hallmark of aberrant S-nitrosylation in HCC and exploit it for therapeutic gain. We find that hepatocyte GSNOR deficiency is characterized by mitochondrial alteration and by marked increases in succinate dehydrogenase (SDH) levels and activity. We find that this depends on the selective S-nitrosylation of Cys(501) in the mitochondrial chaperone TRAP1, which mediates its degradation. As a result, GSNOR-deficient cells and tumors are highly sensitive to SDH inhibition, namely to α-tocopheryl succinate, an SDH-targeting molecule that induced RIP1/PARP1-mediated necroptosis and inhibited tumor growth. Our work provides a specific molecular signature of aberrant S-nitrosylation in HCC, a novel molecular target in SDH, and a first-in-class therapy to treat the disease. Cancer Res; 76(14); 4170-82. ©2016 AACR.
Salvatore Rizza, Claudia Cirotti, Costanza Montagna, Simone Cardaci, Claudia Consales, Mauro Cozzolino, Maria Teresa Carrì, Francesco Cecconi, and Giuseppe Filomeni
Mediators of Inflammation, ISSN: 09629351, eISSN: 14661861, Volume: 2015, Published: 2015 Hindawi Limited
Oxidative and nitrosative stresses have been reported as detrimental phenomena concurring to the onset of several neurodegenerative diseases. Here we reported that the ectopic modulation of the denitrosylating enzymeS-nitrosoglutathione reductase (GSNOR) differently impinges on the phenotype of two SH-SY5Y-basedin vitromodels of neurodegeneration, namely, Parkinson’s disease (PD) and familial amyotrophic lateral sclerosis (fALS). In particular, we provide evidence that GSNOR-knocking down protects SH-SY5Y against PD toxins, while, by contrast, its upregulation is required for G93A-SOD1 expressing cells resistance to NO-releasing drugs. Although completely opposite, both conditions are characterized by Nrf2 localization in the nuclear compartment: in the first case induced by GSNOR silencing, while in the second one underlying the antinitrosative response. Overall, our results demonstrate that GSNOR expression has different effect on neuronal viability in dependence on the stimulus applied and suggest that GSNOR could be a responsive gene downstream of Nrf2 activation.
Costanza Montagna, Giuseppina Di Giacomo, Salvatore Rizza, Simone Cardaci, Elisabetta Ferraro, Paolo Grumati, Daniela De Zio, Emiliano Maiani, Carolina Muscoli, Filomena Lauro, Sara Ilari, Sergio Bernardini, Stefano Cannata, Cesare Gargioli, Maria R. Ciriolo, Francesco Cecconi, Paolo Bonaldo, and Giuseppe Filomeni
Antioxidants and Redox Signaling, ISSN: 15230864, eISSN: 15577716, Pages: 570-587, Published: 1 August 2014 Mary Ann Liebert Inc
AIMS Nitric oxide (NO) production is implicated in muscle contraction, growth and atrophy, and in the onset of neuropathy. However, many aspects of the mechanism of action of NO are not yet clarified, mainly regarding its role in muscle wasting. Notably, whether NO production-associated neuromuscular atrophy depends on tyrosine nitration or S-nitrosothiols (SNOs) formation is still a matter of debate. Here, we aim at assessing this issue by characterizing the neuromuscular phenotype of S-nitrosoglutathione reductase-null (GSNOR-KO) mice that maintain the capability to produce NO, but are unable to reduce SNOs. RESULTS We demonstrate that, without any sign of protein nitration, young GSNOR-KO mice show neuromuscular atrophy due to loss of muscle mass, reduced fiber size, and neuropathic behavior. In particular, GSNOR-KO mice show a significant decrease in nerve axon number, with the myelin sheath appearing disorganized and reduced, leading to a dramatic development of a neuropathic phenotype. Mitochondria appear fragmented and depolarized in GSNOR-KO myofibers and myotubes, conditions that are reverted by N-acetylcysteine treatment. Nevertheless, although atrogene transcription is induced, and bulk autophagy activated, no removal of damaged mitochondria is observed. These events, alongside basal increase of apoptotic markers, contribute to persistence of a neuropathic and myopathic state. INNOVATION Our study provides the first evidence that GSNOR deficiency, which affects exclusively SNOs reduction without altering nitrotyrosine levels, results in a clinically relevant neuromuscular phenotype. CONCLUSION These findings provide novel insights into the involvement of GSNOR and S-nitrosylation in neuromuscular atrophy and neuropathic pain that are associated with pathological states; for example, diabetes and cancer.
Salvatore Rizza, Costanza Montagna, Giuseppina Di Giacomo, Claudia Cirotti, and Giuseppe Filomeni
International Journal of Cell Biology, ISSN: 16878876, eISSN: 16878884, Published: 2014 Hindawi Limited
ProteinS-nitrosation is deemed as a prototype of posttranslational modifications governing cell signaling. It takes place on specific cysteine residues that covalently incorporate a nitric oxide (NO) moiety to formS-nitrosothiol derivatives and depends on the ratio between NO produced by NO synthases and nitrosothiol removal catalyzed by denitrosating enzymes. A large number of cysteine-containing proteins are found to undergoS-nitrosation and, among them, the enzymes catalyzing ubiquitination, mainly the class of ubiquitin E3 ligases and the 20S component of the proteasome, have been reported to be redox modulated in their activity. In this review we will outline the processes regulatingS-nitrosation and try to debate whether and how it affects protein ubiquitination and degradation via the proteasome. In particular, since muscle and neuronal health largely depends on the balance between protein synthesis and breakdown, here we will discuss the impact ofS-nitrosation in the efficiency of protein quality control system, providing lines of evidence and speculating about its involvement in the onset and maintenance of neuromuscular dysfunctions.
P Bernardoni, B Fazi, A Costanzi, R Nardacci, C Montagna, G Filomeni, M R Ciriolo, M Piacentini, and F Di Sano
Cell Death and Disease, eISSN: 20414889, Published: April 2013 Springer Science and Business Media LLC
Endoplasmic reticulum (ER) is the primary site for the synthesis and folding of secreted and membrane-bound proteins. Accumulation of unfolded and misfolded proteins in ER underlies a wide range of human neurodegenerative disorders. Hence, molecules regulating the ER stress response represent potential candidates as drug targets for tackling these diseases. Protein disulphide isomerase (PDI) is a chaperone involved in ER stress pathway, its activity being an important cellular defense against protein misfolding. Here, we demonstrate that human neuroblastoma SH-SY5Y cells overexpressing the reticulon protein 1-C (RTN1-C) reticulon family member show a PDI punctuate subcellular distribution identified as ER vesicles. This represents an event associated with a significant increase of PDI enzymatic activity. We provide evidence that the modulation of PDI localization and activity does not only rely upon ER stress induction or upregulation of its synthesis, but tightly correlates to an alteration in its nitrosylation status. By using different RTN1-C mutants, we demonstrate that the observed effects depend on RTN1-C N-terminal region and on the integrity of the microtubule network. Overall, our results indicate that RTN1-C induces PDI redistribution in ER vesicles, and concomitantly modulates its activity by decreasing the levels of its S-nitrosylated form. Thus RTN1-C represents a promising candidate to modulate PDI function.
Giuseppina Di Giacomo, Salvatore Rizza, Costanza Montagna, and Giuseppe Filomeni
International Journal of Cell Biology, ISSN: 16878876, eISSN: 16878884, Published: 2012 Hindawi Limited
S-nitrosylation is a posttranslational modification of cysteine residues that has been frequently indicated as potential molecular mechanism governing cell response upon redox unbalance downstream of nitric oxide (over)production. In the last years, increased levels ofS-nitrosothiols (SNOs) have been tightly associated with the onset of nitroxidative stress-based pathologies (e.g., cancer and neurodegeneration), conditions in which alterations of mitochondrial homeostasis and activation of cellular processes dependent on it have been reported as well. In this paper we aim at summarizing the current knowledge of mitochondria-related proteins undergoingS-nitrosylation and how this redox modification might impact on mitochondrial functions, whose impairment has been correlated to tumorigenesis and neuronal cell death. In particular, emphasis will be given to the possible, but still neglected implication of denitrosylation reactions in the modulation of mitochondrial SNOs and how they can affect mitochondrion-related cellular process, such as oxidative phosphorylation, mitochondrial dynamics, and mitophagy.