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, Janna F.M. Bogers, Duncan G.G. McMillan, More Authors

Research output: Contribution to journalArticleScientificpeer-review

63 Citations (Scopus)
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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.

Original languageEnglish
Article number4341
Number of pages11
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2019

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