Dimers of mitochondrial ATP synthase form the permeability transition pore

Valentina Giorgio, Sophia Von Stockum, Manuela Antoniel, Astrid Fabbro, Federico Fogolari, Michael Forte, Gary D. Glick, Valeria Petronilli, Mario Zoratti, Ildikó Szabó, Giovanna Lippe, Paolo Bernardi

Research output: Contribution to journalArticlepeer-review


Here we define the molecular nature of the mitochondrial permeability transition pore (PTP), a key effector of cell death. The PTP is regulated by matrix cyclophilin D (CyPD), which also binds the lateral stalkof the F OF1ATP synthase. We show that CyPD binds the oligomycin sensitivity-conferring protein subunit of the enzyme at the same site as the ATP synthase inhibitor benzodiazepine 423 (Bz-423), that Bz-423 sensitizes the PTP to Ca2+ like CyPD itself, and that decreasing oligomycin sensitivity-conferring protein expression by RNAi increases the sensitivity of the PTP to Ca2+. Purified dimers of the ATP synthase, which did not contain voltage-dependent anion channel or adenine nucleotide translocator, were reconstituted into lipid bilayers. In the presence of Ca2+, addition of Bz-423 triggered opening of a channel with currents that were typical of the mitochondrial megachannel, which is the PTP electrophysiological equivalent. Channel openings were inhibited by the ATP synthase inhibitor AMP-PNP (γ-imino ATP,anonhydrolyzable ATP analog) and Mg2+/ADP. These results indicate that the PTP forms from dimers of the ATP synthase.

Original languageEnglish
Pages (from-to)5887-5892
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number15
Publication statusPublished - Apr 9 2013

ASJC Scopus subject areas

  • General


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