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.

Dimers of mitochondrial ATP synthase form the permeability transition pore / Giorgio V.; Von Stockum S.; Antoniel M.; Fabbro A.; Fogolari F.; Forte M.; Glick G.D.; Petronilli V.; Zoratti M.; Szabo I.; Lippe G.; Bernardi P.. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - ELETTRONICO. - 110:15(2013), pp. 5887-5892. [10.1073/pnas.1217823110]

Dimers of mitochondrial ATP synthase form the permeability transition pore

Giorgio V.
Primo
;
2013

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 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.
2013
Dimers of mitochondrial ATP synthase form the permeability transition pore / Giorgio V.; Von Stockum S.; Antoniel M.; Fabbro A.; Fogolari F.; Forte M.; Glick G.D.; Petronilli V.; Zoratti M.; Szabo I.; Lippe G.; Bernardi P.. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - ELETTRONICO. - 110:15(2013), pp. 5887-5892. [10.1073/pnas.1217823110]
Giorgio V.; Von Stockum S.; Antoniel M.; Fabbro A.; Fogolari F.; Forte M.; Glick G.D.; Petronilli V.; Zoratti M.; Szabo I.; Lippe G.; Bernardi P.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/794388
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