Adenine nucleotide translocase-1, a component of the permeability transition pore, can dominantly induce apoptosis

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 o f the mitochondrial permeability transition complex, a protein aggregate co nnecting the inner with the outer mitochondrial membrane that has recently been implicated in apoptosis. ANT-1 expression led to all features of apopt osis, such as phenotypic alterations, collapse of the mitochondrial membran e 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 ind uce apoptosis. Interestingly, ANT-2, a highly homologous protein could not lead to cell death, demonstrating the specificity of the signal for apoptos is induction. In contrast to Bax, a proapoptotic Bcl-2 gene, ANT-1 was unab le to elicit a form of cell death in yeast. This and the observed repressio n of apoptosis by the ANT-1-interacting protein cyclophilin D suggest that the suicidal effect of ANT-1 is mediated by specific protein-protein intera ctions within the permeability transition pore.