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Cited by 98Redox biology and oxidative stressNitric Oxide and Endothelin EffectsMitochondrial Function and Pathology

Nitric oxide and peroxynitrite-dependent aconitase inactivation and iron-regulatory protein-1 activation in mammalian fibroblasts

Castro, Laura A., Robalinho, Raquel L., Cayota, Alfonso, Meneghini, Rogerio, Radi, Rafael·1998·Archives of Biochemistry and Biophysics
DOI 10.1006/abbi.1998.0898
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Abstract

The reaction of reactive oxygen and nitrogen species with the [4Fe-4S]2+ cluster of mitochondrial (m-) and cytosolic (c-) aconitases leads to loss of catalytic activity and, in the case of the c-aconitase, triggers total cluster disruption to yield the iron-regulatory protein-1 (IRP-1). Herein we have studied the relative contribution and interplay of reactive oxygen species (O and H2O2), nitric oxide (*NO), and peroxynitrite in the modulation of m- and c-aconitase and IRP-1 activities in V79-M8 mammalian fibroblasts, identifying key variables that control the various reactivities at the cellular level. Extracellular production of H2O2 led to inactivation of both m- and c-aconitase and IRP-1 activation, while extracellular had no effect. However, increased intracellular production of caused a loss in m- and c-aconitase activity and IRP-1 activation. Nitric oxide released from NOC-12 had a more complex effect on aconitase and IRP-1 activities. Mitochondrial aconitase was more sensitive than c-aconitase to *NO-mediated inactivation and minimal activation of IRP-1 was observed during a 30-min exposure to the *NO donor. The action of *NO was down- or upregulated by the presence of extra- or intracelular, respectively. Extracellular decreased the *NO-mediated inactivation of aconitases, due to the preferential extracellular decomposition and the lower diffusivity of peroxynitrite compared to *NO. On the other hand, *NO exposure concomitant with enhanced intracellular fluxes lead to intracellular peroxynitrite formation as evidenced by Western blot analysis of nitrated proteins, which increased the effects observed with *NO alone. Peroxynitrite-mediated aconitase inactivation, IRP-1 activation, and cellular protein nitration were more pronounced in cells with low GSH content such as V79-M8 glutathione-depleted cells as well as in pGSOD4 cells which contain 32% of the GSH of the parental strain. Mechanistically, our results imply that the differential actions of the studied reactive species toward cellular aconitases depend on at least three critical factors: (i) their reaction rates with aconitases, (ii) the cellular compartment where they are formed, and (iii) the intracellular status of glutathione.

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Authors
Castro, L. A., Robalinho, R. L., Cayota, A., Meneghini, R., & Radi, R.
Affiliations
  • Universidad de la República de Uruguay (UY)
  • Universidade de São Paulo (BR)
ORCID
Venue
Archives of Biochemistry and Biophysics
Publisher
Elsevier BV
Published
1998-11
Volume
359
Issue
2
Pages
215-224
ISSN
0003-9861 (ISSN-L)
DOI
10.1006/abbi.1998.0898
OpenAlex
W1987089638
Cited by
98
References
68
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 2 · 2013: 2 · 2012: 3
FWCI
2.24
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Archives of Biochemistry and Biophysics (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • Comisión Nacional de Investigación Científica y Tecnológica
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
nitric oxide, peroxynitrite, iron regulatory protein 1, [4Fe-4S] cluster, mitochondrial aconitase, cytosolic aconitase, reactive oxygen species, hydrogen peroxide, protein nitration, glutathione, superoxide dismutase, oxidative stress
MeSH terms
Aconitate Hydratase, Animals, Cell Line, Cricetulus, Enzyme Activation, Fibroblasts, Glutathione, Cricetinae, Intracellular Fluid, Iron-Sulfur Proteins, Nitrates, Nitric Oxide, RNA, Messenger, RNA-Binding Proteins, Iron-Regulatory Proteins, Iron Regulatory Protein 1

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