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Mitochondria generated nitric oxide protects against permeability transition via formation of membrane protein

Ana Catarina R Leite1, Helena C F Oliveira, Fabiane L Utino

  • 1Departamento de Fisiologia e Biofísica, Universidade Estadual de Campinas, UNICAMP, Campinas, SP, Brazil.

Biochimica Et Biophysica Acta
|February 9, 2010
PubMed

Insights

Nitric oxide (NO) synthase inhibitors induce mitochondrial permeability transition (MPT) by disrupting mitochondrial function. S-nitrosylation of proteins by NO protects against this MPT, maintaining cellular health.

Area of Science:

  • Mitochondrial Biology
  • Cellular Signaling
  • Biochemistry

Background:

  • Mitochondria-generated nitric oxide (NO) plays a crucial role in regulating vital cellular functions, including energy metabolism, cell cycling, and cell death.
  • Understanding the mechanisms by which NO influences mitochondrial function is essential for comprehending cellular homeostasis and disease pathogenesis.

Purpose of the Study:

  • To investigate the effect of nitric oxide (NO) synthase inhibitors on mitochondrial permeability transition (MPT) in rat liver mitochondria.
  • To elucidate the underlying mechanism of MPT induction by NO synthase inhibitors and the role of S-nitrosylation in mitochondrial protection.

Main Methods:

  • In vitro and in vivo administration of NO synthase inhibitors (L-NAME, L-NNA, L-NMMA) to rat liver mitochondria.
  • Assessment of MPT through cyclosporin A-sensitive mitochondrial membrane potential disruption, mitochondrial swelling, and Ca2+ release.
  • Measurement of NO generation rate, mitochondrial S-nitrosothiol content, and effects of various modulators (Mg2+, ATP, EGTA, catalase, dithiothreitol, SNAP).

Main Results:

  • NO synthase inhibitors induced Ca2+-dependent MPT independently of the organelle's energy state.
  • L-NAME-induced MPT was dose-dependent and sensitive to cyclosporin A, Mg2+/ATP, EGTA, catalase, and dithiothreitol, but not D-NAME.
  • L-NAME treatment decreased NO generation and mitochondrial S-nitrosothiol content, effects reversed by the NO donor SNAP, suggesting a protective role for S-nitrosylation.

Conclusions:

  • NO synthase inhibition triggers MPT in mitochondria, indicating a critical role for NO in maintaining mitochondrial integrity.
  • The protective effect of NO against MPT is proposed to be mediated by S-nitrosylation of critical membrane protein thiols.
  • These findings highlight a novel mechanism by which NO regulates mitochondrial function and protects against cell death pathways.

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