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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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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DOI: https://doi.org/10.1038/sj.onc.1208001
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