Dimers of Mitochondrial ATP Synthase Form the Permeability Transition Pore

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2013 Mar 27

PMID 23530243

Citations 446

Authors

Valentina Giorgio

Sophia von Stockum

Manuela Antoniel

Astrid Fabbro

Federico Fogolari

Michael Forte

Gary D Glick

Valeria Petronilli

Mario Zoratti

Ildiko Szabo

Giovanna Lippe

Paolo Bernardi

Affiliations

Soon will be listed here.

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.

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