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

doi:10.1083/jcb.147.7.1493

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© The Rockefeller University Press, 0021-9525/1999//1493 $5.00
The Journal of Cell Biology, Volume 147, Number 7, , 1999 1493-1502

Original Article

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

Manuel K.A. Bauer^a, Alexis Schubert^a, Oliver Rocks^a, and Stefan Grimm^a

^a Max-Planck-Institute for Biochemistry, 82152 Martinsried, Germany
Max-Planck-Institute for Biochemistry, Am Klopferspitz 18a, 82152 Martinsried, Germany.49-89-8578-388849-89-8578-2219

sgrimm{at}biochem.mpg.de

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 transitioncomplex, a protein aggregate connecting the inner with the outermitochondrial membrane that has recently been implicated inapoptosis. ANT-1 expression led to all features of apoptosis,such as phenotypic alterations, collapse of the mitochondrialmembrane potential, cytochrome c release, caspase activation,and DNA degradation. Both point mutations that impair ANT-1in its known activity to transport ADP and ATP as well as theNH₂-terminal half of the protein could still induce apoptosis.Interestingly, ANT-2, a highly homologous protein could notlead to cell death, demonstrating the specificity of the signalfor apoptosis induction. In contrast to Bax, a proapoptoticBcl-2 gene, ANT-1 was unable to elicit a form of cell deathin yeast. This and the observed repression of apoptosis by theANT-1–interacting protein cyclophilin D suggest that thesuicidal effect of ANT-1 is mediated by specific protein–proteininteractions within the permeability transition pore.

Key Words: cell death • ATP transport • transfection • apoptosis • membrane potential

M.K.A. Bauer and A. Schubert contributed equally to this work.

Abbreviations used in this paper: ANT-1, adenine nucleotidetranslocase-1; CAD, caspase-activated DNase; DCM, dilated cardiomyopathy;FACS, fluorescence-activated cell sorting; GFP, green fluorescentprotein; HA, hemagglutinin; ICAD, inhibitor of caspase-activatedDNase; PARP, poly-ADP-ribose polymerase; PT pore, permeabilitytransition pore.

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