The Adenine Nucleotide Translocase 2, a Mitochondrial Target for Anticancer Biotherapy.

International audienceApoptosis or programmed cell death is one of the most important signaling pathways, which controls the cell fate and is frequently impaired in cancer cells. The major consequences of apoptosis inhibition are the accumulation of mutated cells and their enhanced resistance to chemotherapeutic agents. More generally, intrinsic or acquired apoptosis resistance may favor tumor growth and dissemination of mutated cells, and this resistance can be responsible of treatment failure. Mitochondria are central organelles in the signaling pathway of apoptosis and have been proposed as favorite candidates for anticancer biotherapy because they accommodate potential biological targets. Indeed, although cancer cells are highly glycolytic and become energetically independent of oxidative phosphorylation. Mitochondrial proteins involved in the so-called mitochondrial membrane permeabilization (MMP), such as the adenine nucleotide translocase (ANT) can be instrumental to elicit cancer cell death. Thus, multiple pharmacological and molecular studies revealed ANT could be a promising therapeutic target for the following reasons: (i) ANT is a bi-functional protein, it mediates the vital exchange of cytosolic ADP and mitochondrial ATP and participates to MMP via its capacity to become a lethal pore in the mitochondrial inner membrane; (ii) both ANT functions are under the control of the (anti)-oncogenes from the Bax/Bcl-2 family, (iii) several chemotherapeutic agents directly modulate the pore-forming activity of ANT and (iv) ANT2 isoform, which is anti-apoptotic, can be overexpressed in human cancers and its invalidation sensitize cells to apoptosis. In this review, we will introduce the knowledge of the role of ANT in MMP, illustrate the modulation of ANT by several strategies and propose the possibility to target preferentially the ANT2 isoform for induction of cancer cell apoptosis

Binding of YY1 to the Proximal Region of the Murine Beta Interferon Promoter Is Essential To Allow CBP Recruitment and K8H4/K14H3 Acetylation on the Promoter Region after Virus Infection

Virus-induced activation of the beta interferon (IFN-β) gene requires orderly recruitment of chromatin-remodeling complexes and time-regulated acetylation of histone residues K8H4 and K14H3 on the promoter region. We have previously shown that transcription factor Yin Yang 1 (YY1) binds the murine IFN-β promoter at two sites (−122 and −90) regulating promoter transcriptional capacity with a dual activator/repressor role. In this work we demonstrate that both YY1 −122 and −90 sites are required for CBP recruitment and K8H4/K14H3 acetylation to take place on the IFN-β promoter region after virus infection. A single point mutation introduced at either one of these two sites inhibiting YY1 binding completely disrupted CBP recruitment and K8H4/K14H3 acetylation independently of HMGI or IRF3 binding to the promoter. We have previously demonstrated that YY1 represses the transcriptional capacity of the IFN-β promoter through its −90 site via histone deacetylation. Here we demonstrate that, in vivo, the binding of YY1 to the −90 site is constant all through virus infection whereas the binding of YY1 to the −122 site is activated after infection. We discuss here the capacity of YY1 to either repress (through histone deacetylase recruitment) or activate (through CBP recruitment) IFN-β gene expression according to the occupancy of either only its −90 site or both its −122 and −90 sites

Role of the permeability transition pore complex in lethal crosstalk between endoplasmic reticulum and mitochondria

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Different apoptotic pathways induced by zearalenone,T-2 toxin and ochratoxin A in human hepatoma cells.

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ANT-VDAC1 interaction is direct and depends on ANT isoform conformation in vitro.

International audienceThe voltage-dependent anion channel (VDAC) and the adenine nucleotide translocase (ANT) have central roles in mitochondrial functions such as nucleotides transport and cell death. The interaction between VDAC, an outer mitochondrial membrane protein and ANT, an inner membrane protein, was studied in isolated mitochondria and in vitro. Both proteins were isolated from various mitochondrial sources and reconstituted in vitro using a biomimetic system composed of recombinant human VDAC isoform 1 (rhVDAC1) immobilized on a surface plasmon resonance (SPR) sensor chip surface. Two enriched-preparations of (H)ANT (ANT from heart, mainly ANT1) and (L)ANT (ANT from liver, mainly ANT2) isoforms interacted differently with rhVDAC1. Moreover, the pharmacological ANT inhibitors atractyloside and bongkrekic acid modulated this interaction. Thus, ANT-VDAC interaction depends both on ANT isoform identity and on the conformation of ANT