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Nature 427, 461-465 (29 January 2004) | doi:10.1038/nature02229; Received 14 August 2003; Accepted 10 November 2003

There is a Brief Communications Arising (26 August 2004) associated with this document.

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The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore

Jason E. Kokoszka1,4,6, Katrina G. Waymire1,4, Shawn E. Levy4,6, James E. Sligh4,6, Jiyang Cai5, Dean P. Jones5, Grant R. MacGregor1,2,4 & Douglas C. Wallace1,3,4

  1. Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, California 92697, USA
  2. Department of Developmental and Cell Biology, University of California, Irvine, California 92697, USA
  3. Departments of Biological Chemistry and Ecology and Evolutionary Biology, University of California, Irvine, California 92697, USA
  4. Center for Molecular Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
  5. Departments of Medicine and Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA
  6. Present addresses: Orchid Cellmark, Germantown, Maryland 20874, USA (J.E.K.); Department of Biomedical Informatics (S.E.L.), and Department of Medicine, Dermatology Division (J.E.S.), Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA

Correspondence to: Douglas C. Wallace1,3,4 Correspondence and requests for materials should be addressed to D.C.W. (Email: dwallace@uci.edu).

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A sudden increase in permeability of the inner mitochondrial membrane, the so-called mitochondrial permeability transition, is a common feature of apoptosis and is mediated by the mitochondrial permeability transition pore (mtPTP). It is thought that the mtPTP is a protein complex formed by the voltage-dependent anion channel, members of the pro- and anti-apoptotic BAX-BCL2 protein family, cyclophilin D, and the adenine nucleotide (ADP/ATP) translocators (ANTs)1, 2. The latter exchange mitochondrial ATP for cytosolic ADP and have been implicated in cell death. To investigate the role of the ANTs in the mtPTP, we genetically inactivated the two isoforms of ANT3, 4, 5 in mouse liver and analysed mtPTP activation in isolated mitochondria and the induction of cell death in hepatocytes. Mitochondria lacking ANT could still be induced to undergo permeability transition, resulting in release of cytochrome c. However, more Ca2+ than usual was required to activate the mtPTP, and the pore could no longer be regulated by ANT ligands. Moreover, hepatocytes without ANT remained competent to respond to various initiators of cell death. Therefore, ANTs are non-essential structural components of the mtPTP, although they do contribute to its regulation.