S-nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy

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, Giuseppe Filomeni

Research output: Contribution to journalArticlepeer-review


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 tu-morigenesis 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.

Original languageEnglish
Pages (from-to)E3388-E3397
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number15
Publication statusPublished - Jan 1 2018


  • Aging
  • Mitochondria
  • Mitophagy
  • S-nitrosylation

ASJC Scopus subject areas

  • General


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