The adenine nucleotide translocator: A target of nitric oxide, peroxynitrite, and 4-hydroxynonenal

Helena L A Vieira, Anne Sophie Belzacq, Delphine Haouzi, Francesca Bernassola, Isabel Cohen, Etienne Jacotot, Karine F. Ferri, Chahrazed El Hamel, Laura M. Bartle, Gerry Melino, Catherine Brenner, Victor Goldmacher, Guido Kroemer

Research output: Contribution to journalArticlepeer-review

Abstract

Nitric oxide (NO), peroxynitrite, and 4-hydroxynonenal (HNE) may be involved in the pathological demise of cells via apoptosis. Apoptosis induced by these agents is inhibited by Bcl-2, suggesting the involvement of mitochondria in the death pathway. In vitro, NO, peroxynitrite and HNE can cause direct permeabilization of mitochondrial membranes, and this effect is inhibited by cyclosporin A, indicating involvement of the permeability transition pore complex (PTPC) in the permeabilization event. NO, peroxynitrite and HNE also permeabilize proteoliposomes containing the adenine nucleotide translocator (ANT), one of the key components of the PTPC, yet have no or little effects on protein-free control liposomes. ANT-dependent, NO-, peroxynitrite- or HNE-induced permeabilization is at least partially inhibited by recombinant Bcl-2 protein, as well as the antioxidants trolox and butylated hydroxytoluene. In vitro, none of the tested agents (NO, peroxynitrite, HNE, and tert-butylhydroperoxide) causes preferential carbonylation HNE adduction, or nitrotyrosylation of ANT. However, all these agents induced ANT to undergo thiol oxidation/derivatization. Peroxynitrite and HNE also caused significant lipid peroxidation, which was antagonized by butylated hydroxytoluene but not by recombinant Bcl-2. Transfection-enforced expression of vMIA, a viral apoptosis inhibitor specifically targeted to ANT, largely reduces the mitochondrial and nuclear signs of apoptosis induced by NO, peroxynitrite and HNE in intact cells. Taken together these data suggest that NO, peroxynitrite, and HNE may directly act on ANT to induce mitochondrial membrane permeabilization and apoptosis.

Original languageEnglish
Pages (from-to)4305-4316
Number of pages12
JournalOncogene
Volume20
Issue number32
DOIs
Publication statusPublished - Jul 19 2001

Keywords

  • Apoptosis
  • Bcl-2
  • Mitochondria
  • Permeability transition
  • vMIA

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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