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Purified F-ATP synthase forms a Ca2+-dependent high-conductance channel matching the mitochondrial permeability transition pore

Author

Listed:
  • Andrea Urbani

    (University of Padova)

  • Valentina Giorgio

    (University of Padova
    Consiglio Nazionale delle Ricerche Neuroscience Institute)

  • Andrea Carrer

    (University of Padova)

  • Cinzia Franchin

    (University of Padova
    University of Padova and Azienda Ospedaliera di Padova)

  • Giorgio Arrigoni

    (University of Padova
    University of Padova and Azienda Ospedaliera di Padova)

  • Chimari Jiko

    (Kyoto University)

  • Kazuhiro Abe

    (Nagoya University)

  • Shintaro Maeda

    (Scripps Research Institute)

  • Kyoko Shinzawa-Itoh

    (University of Hyogo)

  • Janna F. M. Bogers

    (Delft University of Technology)

  • Duncan G. G. McMillan

    (Delft University of Technology)

  • Christoph Gerle

    (Osaka University
    Japan Agency for Medical Research and Development (AMED))

  • Ildikò Szabò

    (Consiglio Nazionale delle Ricerche Neuroscience Institute
    University of Padova)

  • Paolo Bernardi

    (University of Padova
    Consiglio Nazionale delle Ricerche Neuroscience Institute)

Abstract

The molecular identity of the mitochondrial megachannel (MMC)/permeability transition pore (PTP), a key effector of cell death, remains controversial. By combining highly purified, fully active bovine F-ATP synthase with preformed liposomes we show that Ca2+ dissipates the H+ gradient generated by ATP hydrolysis. After incorporation of the same preparation into planar lipid bilayers Ca2+ elicits currents matching those of the MMC/PTP. Currents were fully reversible, were stabilized by benzodiazepine 423, a ligand of the OSCP subunit of F-ATP synthase that activates the MMC/PTP, and were inhibited by Mg2+ and adenine nucleotides, which also inhibit the PTP. Channel activity was insensitive to inhibitors of the adenine nucleotide translocase (ANT) and of the voltage-dependent anion channel (VDAC). Native gel-purified oligomers and dimers, but not monomers, gave rise to channel activity. These findings resolve the long-standing mystery of the MMC/PTP and demonstrate that Ca2+ can transform the energy-conserving F-ATP synthase into an energy-dissipating device.

Suggested Citation

  • Andrea Urbani & Valentina Giorgio & Andrea Carrer & Cinzia Franchin & Giorgio Arrigoni & Chimari Jiko & Kazuhiro Abe & Shintaro Maeda & Kyoko Shinzawa-Itoh & Janna F. M. Bogers & Duncan G. G. McMillan, 2019. "Purified F-ATP synthase forms a Ca2+-dependent high-conductance channel matching the mitochondrial permeability transition pore," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12331-1
    DOI: 10.1038/s41467-019-12331-1
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