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

• Published in: The Journal of cell biology 1999-12, Vol.147 (7), p.1493-1501
• Main Authors: Manuel K. A. Bauer, Schubert, Alexis, Rocks, Oliver, Grimm, Stefan
• Format: Article
• Language: English
• Subjects: 3T3 cells; Adenine nucleotide translocase; ADP; Animals; ANT1 gene; ANT2 gene; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Bax gene; Bcl-2 gene; Biochemistry; Cell death; Cell Death - physiology; Cell Division - physiology; Cell Line; Cell lines; Cells; Cricetinae; cyclophilin D; Cyclophilins; cytochrome c; Deoxyribonucleic acid; DNA; Enzymes; Genetic vectors; HeLa cells; Humans; Immunophilins - physiology; Intracellular Membranes - enzymology; Intracellular Membranes - physiology; Membrane Potentials - physiology; Membranes; Mice; Mitochondria; Mitochondria - enzymology; Mitochondria - physiology; Mitochondrial ADP, ATP Translocases - antagonists & inhibitors; Mitochondrial ADP, ATP Translocases - physiology; Original; Peptide Fragments - physiology; Peptidyl-Prolyl Isomerase F; Permeability; Saccharomyces cerevisiae; Saccharomyces cerevisiae - cytology; Saccharomyces cerevisiae - growth & development; Yeasts
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.147.7.1493

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.