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Published on: May 14, 2016
Dynamic evolution of the adenine nucleotide translocase interactome during chemotherapy-induced apoptosis
Florence Verrier1, Aurélien Deniaud, Morgane Lebras
1CNRS FRE 2445, Université de Versailles/St Quentin, 45, avenue des Etats-Unis, Versailles 78035, France.
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 beta 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.
Insights
The adenine nucleotide translocator (ANT) interacts with various proteins, forming a dynamic complex that regulates cell death. Glutathione-S-transferase (GST) acts as a repressor, inhibiting pore opening during apoptosis.
Area of Science:
- Mitochondrial biology
- Cell death pathways
- Molecular interactions
Background:
- The mitochondrial permeability transition pore complex (PTPC) regulates mitochondrial membrane permeabilization during apoptosis, necrosis, and autophagy.
- Adenine nucleotide translocator (ANT) and voltage-dependent anion channel (VDAC) are key PTPC components and targets of proapoptotic inducers.
Purpose of the Study:
- To identify interacting partners of ANT in normal tissues and human cancer cell lines.
- To investigate the dynamic changes in ANT interactions during chemotherapy-induced apoptosis.
Main Methods:
- Co-immunoprecipitation and proteomic analysis were employed to identify ANT-interacting proteins.
- Changes in protein interactions were monitored during apoptosis induction.
Main Results:
- Several ANT-interacting partners were identified, including VDAC, Bax, Bcl-2, respiratory chain subunits, PP2A, PLC beta 4, and IP3 receptor.
- ANT-VDAC interaction remained constant, while other interactions changed during apoptosis.
- Glutathione-S-transferase (GST) interacted with ANT in normal and cancer cells but was lost during apoptosis induction.
- GST's interaction loss suggests its role as an endogenous repressor of PTPC and ANT pore opening.
Conclusions:
- ANT forms a dynamic polyprotein complex with mitochondrial and other organelle proteins (e.g., endoplasmic reticulum).
- Modifications within the ANT interactome are crucial for coordinating cellular responses to apoptotic stimuli.
- GST acts as a repressor of PTPC opening, highlighting its role in regulating cell death.
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