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Dynamic evolution of the adenine nucleotide translocase interactome during chemotherapy-induced apoptosis

Oncogene volume 23, pages 8049–8064 (2004)Cite this article

Abstract

The mitochondrial permeability transition pore complex (PTPC) is involved in the control of the mitochondrial membrane permeabilization during apoptosis, necrosis and autophagy. Indeed, the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC), two major components of PTPC, are the targets of a variety of proapoptotic inducers. Using co-immunoprecipitation and proteomic analysis, we identified some of the interacting partners of ANT in several normal tissues and human cancer cell lines. During chemotherapy-induced apoptosis, some of these interactions were constant (e.g. ANT-VDAC), whereas others changed strongly concomitantly with the dissipation of the mitochondrial transmembrane potential and until nuclear degradation occurred (e.g. Bax, Bcl-2, subunits of the respiratory chain, a subunit of the phosphatase PP2A, phospholipase PLC β 4 and IP3 receptor). In addition, a glutathione-S-transferase (GST) interacts with ANT in normal tissue, in colon carcinoma cells and in vitro. This interaction is lost during apoptosis induction, suggesting that GST behaves as an endogenous repressor of PTPC and ANT pore opening. Thus, ANT is connected to mitochondrial proteins as well as to proteins from other organelles such as the endoplasmic reticulum forming a dynamic polyprotein complex. Changes within this ANT interactome coordinate the lethal response of cells to apoptosis induction.

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Abbreviations

ANT:

adenine nucleotide translocator

ARS:

arsenic trioxide

Atr:

atractyloside

cytochrome c:

Cyt c

DiOC6(3):

3,3′ dihexyloxacarbocyanine iodide

ΔΨm:

mitochondrial transmembrane potential

Etop:

etoposide

HE:

hydroethidine

HK:

hexokinase

LND:

lonidamine

MLP:

melphalan

MMP:

mitochondrial membrane permeabilization

MPT:

mitochondrial permeability transition

MUP:

4-methylumbelliferyl phosphate

IM:

inner membrane

OM:

outer membrane

PI:

propidium iodide

ROS:

reactive oxygen species

PTPC:

permeability transition pore complex

PBR:

peripheral benzodiazepine receptor

GSH:

glutathione

GST:

glutathione-S-transferase

STS:

staurosporine

VDAC:

voltage-dependent anion channel

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Acknowledgements

We thank Dr D Haouzi for helpful discussion and C Henry for her help in mass spectrometry analysis. This work is supported by grants from l'Association pour la Recherche sur le Cancer (ARC), la Fondation pour la Recherche Médicale (FRM), the Ministère délégué à la Recherche et aux Nouvelles Technologies (MRNT) to CB, a special grant by the Ligue contre le Cancer to GK and from INRA, Institut National de la Recherche Agronomique to GJ. FV and AD were supported by fellowships from the MRNT. MLB receives a postdoctoral fellowship from the Centre National de la Recherche Scientifique (CNRS).

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Authors and Affiliations

  1. CNRS FRE 2445, Université de Versailles/St Quentin, 45, avenue des Etats-Unis, Versailles, 78035, France

    Florence Verrier, Aurélien Deniaud, Morgane LeBras, Bernard Mignotte & Catherine Brenner

  2. CNRS UMR 8125, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, 94805, France

    Didier Métivier & Guido Kroemer

  3. Institut National de la Recherche Agronomique, UR 121, Laboratoire de Recherches de Technologie Laitière, Rennes Cedex, 35042, France

    Gwenaël Jan

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Correspondence to Catherine Brenner.

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Verrier, F., Deniaud, A., LeBras, M. et al. Dynamic evolution of the adenine nucleotide translocase interactome during chemotherapy-induced apoptosis. Oncogene 23, 8049–8064 (2004). https://doi.org/10.1038/sj.onc.1208001

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