title: Dimers of mitochondrial ATP synthase form the permeability transition pore.
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.
authors.affiliation: Consiglio Nazionale delle Ricerche Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35121 Padua, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Giorgio
authors.forename: Sophia
authors.initials: S
authors.lastname: von Stockum
authors.forename: Manuela
authors.initials: M
authors.lastname: Antoniel
authors.forename: Astrid
authors.initials: A
authors.lastname: Fabbro
authors.forename: Federico
authors.initials: F
authors.lastname: Fogolari
authors.forename: Michael
authors.initials: M
authors.lastname: Forte
authors.forename: Gary D
authors.initials: GD
authors.lastname: Glick
authors.forename: Valeria
authors.initials: V
authors.lastname: Petronilli
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
authors.forename: Ildikó
authors.initials: I
authors.lastname: Szabó
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lippe
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D019281:Dimerization; D006801:Humans; D006868:Hydrolysis; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology*; D000083162:Mitochondrial Permeability Transition Pore; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D034741:RNA, Small Interfering; D025261:Mitochondrial Proton-Translocating ATPases; D002118:Calcium