Purified F-ATP synthase forms a Ca2+-dependent high-conductance channel matching the mitochondrial permeability transition pore
Year: 2019
Type: article
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.
Source: Nature Communications
Institutions: University of Padua, National Research Council, Azienda Ospedale - Università Padova, Kyoto University, Institute for Integrated Radiation and Nuclear Science, Kyoto University, Nagoya University, Scripps Research Institute, University of Hyogo, Delft University of Technology, Japan Agency for Medical Research and Development, The University of Osaka
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: Naito Foundation, Japan Agency for Medical Research and Development, Fondation Leducq, Ministry of Education, Culture, Sports, Science and Technology, Associazione Italiana per la Ricerca sul Cancro, Japan Society for the Promotion of Science, Core Research for Evolutional Science and Technology
Awards: G1131291722, Structural physiology of the gastric proton pump, G2576085165, G319085104, G3372736950, Targeting Mitochondria to Treat Heart Disease, G409892549, G4222593993, G6718509927, G7154820356, G7305684116, High resolution and dynamic structural analysis of the entire mammalian FoF1ATP synthase, Single particle cryoEM of mammalian FoF1 ATP synthase, G7879866177, High-resolution structural analysis of mitochondrial supercomplex and ATP synthase involved in ATP synthesis, G8571295246, G8666310399
OpenAlex ID: W2976241964