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 journalArticle

489 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5887-5892
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number15
DOIs
StatePublished - Apr 9 2013

Fingerprint

Mitochondrial Proton-Translocating ATPases
Permeability
Adenosine Triphosphate
Benzodiazepines
Voltage-Dependent Anion Channels
Adenylyl Imidodiphosphate
Adenine Nucleotides
Protein Subunits
Lipid Bilayers
RNA Interference
Adenosine Diphosphate
Cell Death
Enzymes

ASJC Scopus subject areas

  • General

Cite this

Dimers of mitochondrial ATP synthase form the permeability transition pore. / Giorgio, Valentina; Von Stockum, Sophia; Antoniel, Manuela; Fabbro, Astrid; Fogolari, Federico; Forte, Michael; Glick, Gary D.; Petronilli, Valeria; Zoratti, Mario; Szabó, Ildikó; Lippe, Giovanna; Bernardi, Paolo.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 15, 09.04.2013, p. 5887-5892.

Research output: Contribution to journalArticle

Giorgio, V, Von Stockum, S, Antoniel, M, Fabbro, A, Fogolari, F, Forte, M, Glick, GD, Petronilli, V, Zoratti, M, Szabó, I, Lippe, G & Bernardi, P 2013, 'Dimers of mitochondrial ATP synthase form the permeability transition pore', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 15, pp. 5887-5892. https://doi.org/10.1073/pnas.1217823110
Giorgio, Valentina ; Von Stockum, Sophia ; Antoniel, Manuela ; Fabbro, Astrid ; Fogolari, Federico ; Forte, Michael ; Glick, Gary D. ; Petronilli, Valeria ; Zoratti, Mario ; Szabó, Ildikó ; Lippe, Giovanna ; Bernardi, Paolo. / Dimers of mitochondrial ATP synthase form the permeability transition pore. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 15. pp. 5887-5892.
@article{a3e9fb3850dd447c882dac7feb76161b,
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 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.",
author = "Valentina Giorgio and {Von Stockum}, Sophia and Manuela Antoniel and Astrid Fabbro and Federico Fogolari and Michael Forte and Glick, {Gary D.} and Valeria Petronilli and Mario Zoratti and Ildik{\'o} Szab{\'o} and Giovanna Lippe and Paolo Bernardi",
year = "2013",
month = "4",
day = "9",
doi = "10.1073/pnas.1217823110",
language = "English (US)",
volume = "110",
pages = "5887--5892",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "15",

}

TY - JOUR

T1 - Dimers of mitochondrial ATP synthase form the permeability transition pore

AU - Giorgio, Valentina

AU - Von Stockum, Sophia

AU - Antoniel, Manuela

AU - Fabbro, Astrid

AU - Fogolari, Federico

AU - Forte, Michael

AU - Glick, Gary D.

AU - Petronilli, Valeria

AU - Zoratti, Mario

AU - Szabó, Ildikó

AU - Lippe, Giovanna

AU - Bernardi, Paolo

PY - 2013/4/9

Y1 - 2013/4/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84876031864&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876031864&partnerID=8YFLogxK

U2 - 10.1073/pnas.1217823110

DO - 10.1073/pnas.1217823110

M3 - Article

VL - 110

SP - 5887

EP - 5892

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 15

ER -