Dimers of mitochondrial ATP synthase form the permeability transition pore.

TitleDimers of mitochondrial ATP synthase form the permeability transition pore.
Publication TypeJournal Article
Year of Publication2013
AuthorsGiorgio, V, von Stockum, S, Antoniel, M, Fabbro, A, Fogolari, F, Forte, M, Glick, GD, Petronilli, V, Zoratti, M, Szabó, I, Lippe, G, Bernardi, P
JournalProc Natl Acad Sci U S A
Volume110
Issue15
Pagination5887-92
Date Published2013 Apr 09
ISSN1091-6490
KeywordsAnimals, Apoptosis, Calcium, Cattle, Cell Line, Tumor, Dimerization, Humans, Hydrolysis, Membrane Potentials, Mice, Mitochondria, Mitochondria, Liver, Mitochondrial Membrane Transport Proteins, Mitochondrial Proton-Translocating ATPases, RNA, Small Interfering, Transfection
Abstract

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 stalk of the FOF1 ATP 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 Ca(2+) like CyPD itself, and that decreasing oligomycin sensitivity-conferring protein expression by RNAi increases the sensitivity of the PTP to Ca(2+). 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 Ca(2+), 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, a nonhydrolyzable ATP analog) and Mg(2+)/ADP. These results indicate that the PTP forms from dimers of the ATP synthase.

DOI10.1073/pnas.1217823110
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
Citation Key10.1073/pnas.1217823110
PubMed ID23530243
PubMed Central IDPMC3625323
Grant ListGGP11082 / / Telethon / Italy
R01 GM069883 / GM / NIGMS NIH HHS / United States
1R01GM069883 / GM / NIGMS NIH HHS / United States