Adenine Nucleotide Translocase-1, a Component of the Permeability Transition Pore, Can Dominantly Induce Apoptosis

Abstract

Here, we describe the isolation of adenine nucleotide translocase-1 (ANT-1) in a screen for dominant, apoptosis-inducing genes. ANT-1 is a component of the mitochondrial permeability transition complex, a protein aggregate connecting the inner with the outer mitochondrial membrane that has recently been implicated in apoptosis. ANT-1 expression led to all features of apoptosis, such as phenotypic alterations, collapse of the mitochondrial membrane potential, cytochrome c release, caspase activation, and DNA degradation. Both point mutations that impair ANT-1 in its known activity to transport ADP and ATP as well as the NH2-terminal half of the protein could still induce apoptosis. Interestingly, ANT-2, a highly homologous protein could not lead to cell death, demonstrating the specificity of the signal for apoptosis induction. In contrast to Bax, a proapoptotic Bcl-2 gene, ANT-1 was unable to elicit a form of cell death in yeast. This and the observed repression of apoptosis by the ANT-1–interacting protein cyclophilin D suggest that the suicidal effect of ANT-1 is mediated by specific protein–protein interactions within the permeability transition pore.

Adeno-associated virus-mediated gene transfer of the heart/muscle adenine nucleotide translocator (ANT) in mouse

“…25 Reduction of ANT1 activity in either the mutant mice or in ANT1-mutant PEO patients has not been observed to increase apoptosis, 26 whereas ANT1 expression due to Ant1 cDNA transfection into nonmyogenic cultured cells has been reported to induce apoptosis. 27 However, our data suggest that increased apoptosis may not be a concern during the transduction of skeletal muscle with the Ant1 cDNA. This is because myoblasts, myotubes, skeletal muscle and heart all naturally express high levels of ANT1 and thus must be resistant to any proapoptotic effects that this protein might have.…”

The permeability transition pore in cell death

“…However, a substantial body of evidence indicates that cypD has anti-apoptotic activities. Importantly, we [120,121] and others [122] have recently found that enforced cypD expression can specifically repress the activation of the PT-pore. Another study in neuronal cells also observed apoptosis inhibition (but sensitisation for necrosis) by cypD overexpression [123].…”

Adenine nucleotide translocase family: four isoforms for apoptosis modulation in cancer

“…Pharmacological studies with CAT and BA suggest that induction of the pore function might be an irreversible process (C Brenner, unpublished data). Interestingly, only the first third of the protein is involved in apoptosis (Bauer et al, 1999) and more precisely, the region 105-156 of ANT2 has been suggested to be the binding domain of ANT with several proteins such as Bax and Bcl-2 (reviewed in Jacotot et al, 2006). Therefore, it is tempting to postulate that direct interaction of ligands with specific amino acids contained within the ANT sequence provokes a conformational change resulting in a switch from the translocase function to the pore function.…”

“…More recently, a third major breakthrough has been made in terms of role of ANT in apoptosis. Thus, ANT is expressed as four tissue-specific isoforms, ANT1 to ANT4, and we and others postulated that each ANT isoform might have a specific role in influencing cell fate, notably in cancer cells (Bauer et al, 1999;Zamora et al, 2004a;Le Bras et al, 2006;Gallerne et al, 2010). In this review, we recapitulate our knowledge of the role that the various isoforms of ANT play in apoptosis, examine the expression and the function of the four ANT isoforms in cancer cells and discuss recent evidence to propose a novel classification of ANT isoforms and their function in cancer cell death.…”