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

Nature volume 427, pages 461–465 (2004)Cite this article

Abstract

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.

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Figure 1: Preparation of a CRE-conditional Ant2-null mutant allele in mouse embryonic stem cells.
Figure 2: Inactivation of ANT in liver mitochondria.
Figure 3: Effect of ANT-deficiency on mtPTP activation in liver mitochondria.
Figure 4: Induction of cell death in ANT-deficient mouse hepatocytes.

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Acknowledgements

We thank M. Magnuson for providing the Alb-Cre transgenic mice, L. Hayes for mouse husbandry and genotyping, and H. Yi for the electron microscope analysis. This work was funded by US National Institutes of Health grants awarded to D.C.W., G.R.M. and D.P.J.

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Author notes

  1. Jason E. Kokoszka

    Present address: Orchid Cellmark, Germantown, Maryland, 20874, USA

  2. Shawn E. Levy

    Present address: Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA

  3. James E. Sligh

    Present address: Department of Medicine, Dermatology Division, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA

Authors and Affiliations

  1. Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, California, 92697, USA

    Jason E. Kokoszka, Katrina G. Waymire, Grant R. MacGregor & Douglas C. Wallace

  2. Department of Developmental and Cell Biology, University of California, Irvine, California, 92697, USA

    Grant R. MacGregor

  3. Departments of Biological Chemistry and Ecology and Evolutionary Biology, University of California, Irvine, California, 92697, USA

    Douglas C. Wallace

  4. Center for Molecular Medicine, Emory University School of Medicine, Atlanta, Georgia, 30322, USA

    Jason E. Kokoszka, Katrina G. Waymire, Shawn E. Levy, James E. Sligh, Grant R. MacGregor & Douglas C. Wallace

  5. Departments of Medicine and Biochemistry, Emory University School of Medicine, Atlanta, Georgia, 30322, USA

    Jiyang Cai & Dean P. Jones

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Correspondence to Douglas C. Wallace.

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Competing interests

J.E.K., K.G.W., S.E.L., J.E.S., G.R.M. and D.C.W. hold stock in a mitochondrial disease company, Medergy, Inc. but only D.C.W. holds significant equity as the scientific founder. The financial goals of the company do not conflict with the scientific content of this paper.

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Kokoszka, J., Waymire, K., Levy, S. et al. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427, 461–465 (2004). https://doi.org/10.1038/nature02229

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