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.