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

H L Vieira1, A S Belzacq, D Haouzi

  • 1Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.

Oncogene
|July 24, 2001
PubMed

Insights

Nitric oxide (NO), peroxynitrite, and 4-hydroxynonenal (HNE) induce apoptosis by permeabilizing mitochondrial membranes. These reactive species directly target the adenine nucleotide translocator (ANT), a key component of the permeability transition pore complex (PTPC).

Area of Science:

  • Cell Biology
  • Biochemistry
  • Toxicology

Background:

  • Nitric oxide (NO), peroxynitrite, and 4-hydroxynonenal (HNE) are implicated in apoptosis.
  • Bcl-2 inhibits apoptosis induced by these agents, suggesting mitochondrial involvement.
  • Mitochondrial membrane permeabilization is a critical step in apoptosis.

Purpose of the Study:

  • To investigate the direct role of NO, peroxynitrite, and HNE in mitochondrial membrane permeabilization.
  • To identify the specific molecular targets of these agents in the apoptosis pathway.
  • To elucidate the involvement of the adenine nucleotide translocator (ANT) and the permeability transition pore complex (PTPC).

Main Methods:

  • In vitro studies using proteoliposomes containing ANT.
  • Assessment of mitochondrial membrane permeabilization.
  • Analysis of ANT modifications (thiol oxidation, carbonylation, adduction).
  • Cell-based assays with vMIA transfection to inhibit apoptosis.

Main Results:

  • NO, peroxynitrite, and HNE directly permeabilize mitochondrial membranes and ANT-containing proteoliposomes.
  • These effects are inhibited by cyclosporin A, trolox, butylated hydroxytoluene, and Bcl-2.
  • Agents induce thiol oxidation/derivatization of ANT but not direct carbonylation or nitrotyrosylation.
  • vMIA expression significantly reduces apoptosis in cells treated with these agents.

Conclusions:

  • NO, peroxynitrite, and HNE directly target ANT, leading to PTPC-mediated mitochondrial membrane permeabilization.
  • This mechanism contributes to the induction of apoptosis by these reactive species.
  • ANT is a key molecular player in the mitochondrial pathway of apoptosis induced by NO, peroxynitrite, and HNE.

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