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

Oncogene volume 20, pages 4305–4316 (2001)Cite this article

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.

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Abbreviations

AIF:

apoptosis-inducing factor

ANT:

adenine nucleotide translocator

COX:

cytochrome c oxidase

CsA:

cyclosporin A

Cyt c:

cytochrome c

DiOC6(3):

3,3′dihexyloxacarbocyanine iodide

ΔΨm:

mitochondral transmembrane poteintal

BHT:

butylated hydroxytoluene

HE:

hydroethidine

HNE:

4-hydroxynonenal

4-MU:

4-methylumbelliferone

4-MUP:

4-methylumbelliferylphosphate

ROS:

reactive oxygen species

SIN-1:

3-morpholinosydnonimine

SNAP:

S-nitroso-N-acetylpenicillamine

PTPC:

permeability transition pore

SOD:

superoxide dismutase

t-BHP:

tert-butyhlhydroperoxide

VDAC:

voltage-dependent anion channel

vMIA:

viral mitochondria-localized inhibitor of apoptosis

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Acknowledgements

We thank Dr Nicole Israel (Pasteur Institute, Paris) for Bcl-2 transfected Jurkat cells, Z Xie and JC Reed (Burnham Institute, La Jolla, CA, USA) for recombinant Bcl-2, Dr MP Mattson (NIH, Bethesda, USA) for anti-HNE antibody, and D Métivier (CNRS, Villejuif, France) for cytofluorometric analyses. This work has been supported by a special grant from the Ligue Nationale contre le Cancer, Comité Val de Marne de la Ligue contre le Cancer, as well as grants from ANRS (to G Kroemer), FRM (to G Kroemer and C Brenner), and the European Commission Grant No. QL61-1999-00739 (to G Kroemer and G Melino). HLA Vieira receives a fellowship from the Fundação para a Ciência e a Tecnologia PRAXIS XXI, Portugal; A-S Belzacq from ARC, E Jacotot from ANRS.

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Authors and Affiliations

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

    Helena LA Vieira, Delphine Haouzi, Isabel Cohen, Etienne Jacotot, Karine F Ferri, Chahrazed El Hamel, Catherine Brenner & Guido Kroemer

  2. CNRS-UMR6022, Université de Technologie de Compiègne, BP 20529, F-60205 Compiègne, France

    Anne-Sophie Belzacq & Catherine Brenner

  3. Biochemistry Laboratory, University of Rome Tor Vergata, Rome, 00133, Italy

    Francesca Bernassola & Gerry Melino

  4. Apoptosis Technology, Inc., 148 Sidney Street, Cambridge, 02139, Massachusetts MA, USA

    Laura M Bartle & Victor Goldmacher

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Correspondence to Guido Kroemer.

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Vieira, H., Belzacq, AS., Haouzi, D. et al. The adenine nucleotide translocator: a target of nitric oxide, peroxynitrite, and 4-hydroxynonenal. Oncogene 20, 4305–4316 (2001). https://doi.org/10.1038/sj.onc.1204575

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