Differential role of superoxide and glutathione in S-nitrosoglutathione-mediated apoptosis: A rationale for mild forms of familial amyotrophic lateral sclerosis associated with less active Cu,Zn superoxide dismutase mutants

Maria Rosa Ciriolo, Katia Aquilano, Angelo De Martino, Maria Teresa Carrì, Giuseppe Rotilio

Research output: Contribution to journalArticlepeer-review

Abstract

SH-SY5Y cells transfected with the enzymatically inactive Cu,Zn superoxide dismutase mutant H46R were more resistant to S-nitrosoglutathione (GSNO)-induced apoptosis. Cytochrome c release from mitochondria, caspase 3 activation, p53 up-regulation, p21 cleavage and Bcl-2 modulation, all involved in the apoptotic process, were significantly less altered with respect to untransfected cells. The H46R resistance to NO was associated with a higher content of reduced glutathione (GSH) and was abolished by blockage of glutathione synthesis. On the other hand, H46R cells were as sensitive as SH-SY5Y cells to puromycin-induced apoptosis; furthermore, they were more susceptible to apoptosis elicited by the superoxide-generating drug paraquat and to cell necrosis provoked by t-butyl hydroperoxide. These results confirm that the level of superoxide dismutase activity is fundamental for protecting cells against oxygen free radical challenge. Its impairment is not detrimental to cells exposed to NO, as long as the overall reducing power represented by GSH is assured. These results are relevant to explain a milder progression of the familial amyotrophic lateral sclerosis disease when associated with the H46R mutation.

Original languageEnglish
Pages (from-to)1433-1443
Number of pages11
JournalJournal of Neurochemistry
Volume77
Issue number6
DOIs
Publication statusPublished - 2001

Keywords

  • Apoptosis
  • Cu,Zn superoxide dismutase
  • Familial amyotrophic lateral sclerosis
  • Glutathione
  • Nitric oxide
  • p53/p21 pathway

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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