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

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, Christoph Gerle (), Ildikò Szabò () and Paolo Bernardi ()
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Andrea Urbani: University of Padova
Valentina Giorgio: University of Padova
Andrea Carrer: University of Padova
Cinzia Franchin: University of Padova
Giorgio Arrigoni: University of 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
Ildikò Szabò: Consiglio Nazionale delle Ricerche Neuroscience Institute
Paolo Bernardi: University of Padova

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12331-1

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