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,Ildikò Szabò,Giovanna Lippe,Paolo Bernardi +11 more
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It is shown 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), which sensitizes the PTP to Ca2+.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 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, a nonhydrolyzable ATP analog) and Mg2+/ADP. These results indicate that the PTP forms from dimers of the ATP synthase.read more
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Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.
Lorenzo Galluzzi,Lorenzo Galluzzi,Ilio Vitale,Stuart A. Aaronson,John M. Abrams,Dieter Adam,Patrizia Agostinis,Emad S. Alnemri,Lucia Altucci,Ivano Amelio,David W. Andrews,David W. Andrews,Margherita Annicchiarico-Petruzzelli,Alexey V. Antonov,Eli Arama,Eric H. Baehrecke,Nickolai A. Barlev,Nicolas G. Bazan,Francesca Bernassola,Mathieu J.M. Bertrand,Katiuscia Bianchi,Mikhail V. Blagosklonny,Klas Blomgren,Christoph Borner,Patricia Boya,Catherine Brenner,Catherine Brenner,Michelangelo Campanella,Eleonora Candi,Didac Carmona-Gutierrez,Francesco Cecconi,Francis Ka-Ming Chan,Navdeep S. Chandel,Emily H. Cheng,Jerry E. Chipuk,John A. Cidlowski,Aaron Ciechanover,Gerald M. Cohen,Marcus Conrad,Juan R. Cubillos-Ruiz,Peter E. Czabotar,Peter E. Czabotar,Vincenzo D'Angiolella,Ted M. Dawson,Valina L. Dawson,Vincenzo De Laurenzi,Ruggero De Maria,Klaus-Michael Debatin,Ralph J. DeBerardinis,Mohanish Deshmukh,Nicola Di Daniele,Francesco Di Virgilio,Vishva M. Dixit,Scott J. Dixon,Colin S. Duckett,Brian David Dynlacht,Wafik S. El-Deiry,John W. Elrod,Gian Maria Fimia,Simone Fulda,Simone Fulda,Ana J. García-Sáez,Abhishek D. Garg,Carmen Garrido,Carmen Garrido,Evripidis Gavathiotis,Pierre Golstein,Eyal Gottlieb,Eyal Gottlieb,Douglas R. Green,Lloyd A. Greene,Hinrich Gronemeyer,Atan Gross,György Hajnóczky,J. Marie Hardwick,Isaac S. Harris,Michael O. Hengartner,Claudio Hetz,Hidenori Ichijo,Marja Jäättelä,Bertrand Joseph,Philipp J. Jost,Philippe Juin,William J. Kaiser,Michael Karin,Thomas Kaufmann,Oliver Kepp,Adi Kimchi,Richard N. Kitsis,Daniel J. Klionsky,Richard A. Knight,Sharad Kumar,Sam W. Lee,John J. Lemasters,Beth Levine,Andreas Linkermann,Stuart A. Lipton,Richard A. Lockshin,Richard A. Lockshin,Carlos López-Otín,Scott W. Lowe,Scott W. Lowe,Tom Luedde,Enrico Lugli,Marion MacFarlane,Frank Madeo,Michal Malewicz,Walter Malorni,Gwenola Manic,Jean-Christophe Marine,Seamus J. Martin,Jean-Claude Martinou,Jan Paul Medema,Patrick Mehlen,Pascal Meier,Sonia Melino,Edward A. Miao,Jeffery D. Molkentin,Ute M. Moll,Cristina Muñoz-Pinedo,Shigekazu Nagata,Gabriel Núñez,Andrew Oberst,Moshe Oren,Michael Overholtzer,Michele Pagano,Theocharis Panaretakis,Theocharis Panaretakis,Manolis Pasparakis,Josef M. Penninger,David M. Pereira,Shazib Pervaiz,Marcus E. Peter,Mauro Piacentini,Paolo Pinton,Jochen H. M. Prehn,Hamsa Puthalakath,Gabriel A. Rabinovich,Markus Rehm,Rosario Rizzuto,Cecília M. P. Rodrigues,David C. Rubinsztein,Thomas Rudel,Kevin M. Ryan,Emre Sayan,Luca Scorrano,Feng Shao,Yufang Shi,Yufang Shi,John Silke,John Silke,Hans-Uwe Simon,Antonella Sistigu,Brent R. Stockwell,Andreas Strasser,Gyorgy Szabadkai,Gyorgy Szabadkai,Gyorgy Szabadkai,Stephen W.G. Tait,Daolin Tang,Daolin Tang,Nektarios Tavernarakis,Andrew Thorburn,Yoshihide Tsujimoto,Boris Turk,Tom Vanden Berghe,Peter Vandenabeele,Matthew G. Vander Heiden,Matthew G. Vander Heiden,Andreas Villunger,Herbert W. Virgin,Karen H. Vousden,Domagoj Vucic,Erwin F. Wagner,Henning Walczak,David Wallach,Ying Wang,James A. Wells,Will Wood,Junying Yuan,Zahra Zakeri,Boris Zhivotovsky,Boris Zhivotovsky,Laurence Zitvogel,Gerry Melino,Gerry Melino,Guido Kroemer +186 more
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