Dimers of mitochondrial ATP synthase form the permeability transition pore

作者：Giorgio, Valentina; von Stockum, Sophia; Antoniel, Manuela; Fabbro, Astrid; Fogolari, Federico; Forte, Michael; Glick, Gary D.; Petronilli, Valeria; Zoratti, Mario; Szabo, Ildiko; Lippe, Giovanna^*; Bernardi, Paolo

来源：Proceedings of the National Academy of Sciences, 2013, 110(15): 5887-5892.

DOI：10.1073/pnas.1217823110

• CA-2&-INDUCED MEMBRANE TRANSITION
• CYCLOPHILIN-D
• CYCLOSPORINE-A
• F(0)F(1)ATP SYNTHASE
• MOLECULAR TARGET
• CHANNEL ACTIVITY
• ADP/ATP CARRIER
• INNER MEMBRANE
• IN-VITRO
• INHIBITOR

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 (gamma-imino ATP, a nonhydrolyzable ATP analog) and Mg2+/ADP. These results indicate that the PTP forms from dimers of the ATP synthase.

• 出版日期2013-4-9