Dimers of mitochondrial ATP synthase form the permeability transition pore

By V. Giorgio, S. von Stockum, Manuela Antoniel, A. Fabbro, Federico Fogolari, M. Forte, G. Glick, V. Petronilli, M. Zoratti, I. Szabó and 2 more. Proceedings of the National Academy of Sciences of the United States of America, 2013

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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.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a8bdf2f1807f901315b9f1ee3df2de5c2faab5eb

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Citations in the corpus

The emerging role of Nrf2 in mitochondrial function (2015, background): “The mPTP, a complex that allows the mitochondrial inner membrane to become permeable to molecules with masses up to 1500 Da, was recently identified to be formed from dimers of the F0F1-ATP synthase [101].”
Metabolic control of cell death (2014, background): “In stringent conditions of coimmunoprecipitation, CYPD interacts with the oligomycin sensitivity–conferring protein (OSCP) but not with other subunits of the F1FO-ATP synthase lateral stalk (29).”
Mitochondrial function as a therapeutic target in heart failure (2016, neutral): “The MPTP seems to be comprised of ATP synthase (complex V) dimers and to be gated by mitochondrial matrix calcium content via cyclophillin D 186,187 .”
Neuronal calcium signaling: function and dysfunction (2014, background): “Its recent molecular identification has revealed that it is part of the ATP synthase complex, thus further strengthening the link between mitochondrial Ca2+ and energy balance [91, 92].”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “Initially, the c-ring of the F1FO ATPase [395–398] as well as F1FO ATPase dimers [399] have been proposed to constitute the long-sought PTPC pore-forming unit.”
Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. (2014, background): “While the molecular identity of the mPTP needs to be validated in detail (157, 217, 494), the presence of bcl-2/bcl-xL or phosphorylated glycogen synthase kinase 3 (P-GSK-3 ) in the vicinity of the pore or attachment of hexokinase II desensitize the pore to oxidants (86, 217, 218) and extend the tim”
Neuronal Cell Death. (2018, positive): “To form a pore in mitochondrial inner membrane, cyclophilin D must interact with one or several transmembrane proteins such as the adenine nucleotide carrier, the phosphate carrier (270), the F0F1ATP synthase (251), and/or the spastic paraplegia protein 7 (SPG7) (619).”