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ATP Synthase

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Vilma Kaplanová – 1st expert on this subject based on the ideXlab platform

  • TMEM70 mutations cause isolated ATP Synthase deficiency and neonatal mitochondrial encephalocardiomyopathy
    Nature Genetics, 2008
    Co-Authors: Alena Čížková, Viktor Stránecký, Johannes A Mayr, Markéta Tesařová, Vendula Havlíčková, Jan Paul, Robert Ivánek, Andreas W Kuss, Hana Hansíková, Vilma Kaplanová

    Abstract:

    We carried out whole-genome homozygosity mapping, gene expression analysis and DNA sequencing in individuals with isolated mitochondrial ATP Synthase deficiency and identified disease-causing mutations in TMEM70 . Complementation of the cell lines of these individuals with wild-type TMEM70 restored biogenesis and metabolic function of the enzyme complex. Our results show that TMEM70 is involved in mitochondrial ATP Synthase biogenesis in higher eukaryotes. Stanislav Kmoch and colleagues identify mutations in TMEM70 in individuals with isolated mitochondrial ATP Synthase deficiency, and demonstrate that complementation of cell lines of affected individuals with wild-type TMEM70 restores ATP Synthase function.

  • tmem70 mutations cause isolated ATP Synthase deficiency and neonatal mitochondrial encephalocardiomyopathy
    Nature Genetics, 2008
    Co-Authors: Alena Cizkova, Viktor Stránecký, Johannes A Mayr, Vendula Havlíčková, Jan Paul, Robert Ivánek, Andreas W Kuss, Hana Hansíková, Marketa Tesarova, Vilma Kaplanová

    Abstract:

    We carried out whole-genome homozygosity mapping, gene expression analysis and DNA sequencing in individuals with isolated mitochondrial ATP Synthase deficiency and identified disease-causing mutations in TMEM70. Complementation of the cell lines of these individuals with wild-type TMEM70 restored biogenesis and metabolic function of the enzyme complex. Our results show that TMEM70 is involved in mitochondrial ATP Synthase biogenesis in higher eukaryotes.

Jean Velours – 2nd expert on this subject based on the ideXlab platform

  • Evidence of the Proximity of ATP Synthase Subunits 6 (a) in the Inner Mitochondrial Membrane and in the Supramolecular Forms of Saccharomyces cerevisiae ATP Synthase
    Journal of Biological Chemistry, 2011
    Co-Authors: Jean Velours, Alain Dautant, Claire Stines-chaumeil, Johan Habersetzer, Stéphane Chaignepain, Daniel Brèthes

    Abstract:

    The involvement of subunit 6 (a) in the interface between yeast ATP Synthase monomers has been highlighted. Based on the formation of a disulfide bond and using the unique cysteine 23 as target, we show that two subunits 6 are close in the inner mitochondrial membrane and in the solubilized supramolecular forms of the yeast ATP Synthase. In a null mutant devoid of supernumerary subunits e and g that are involved in the stabilization of ATP Synthase dimers, ATP Synthase monomers are close enough in the inner mitochondrial membrane to make a disulfide bridge between their subunits 6, and this proximity is maintained in detergent extract containing this enzyme. The cross-linking of cysteine 23 located in the N-terminal part of the first transmembrane helix of subunit 6 suggests that this membrane-spanning segment is in contact with its counterpart belonging to the ATP Synthase monomer that faces it and participates in the monomer-monomer interface.

  • mitochondrial f1f0 ATP Synthase and organellar internal architecture
    The International Journal of Biochemistry & Cell Biology, 2009
    Co-Authors: Jean Velours, Alain Dautant, Benedicte Salin, Isabelle Sagot, Daniel Brèthes

    Abstract:

    Abstract The mitochondrial F1F0-ATP Synthase adopts supramolecular structures. The interaction domains between monomers involve components belonging to the F0 domains. In Saccharomyces cerevisiae, alteration of these components destabilizes the oligomeric structures, leading concomitantly to the appearance of monomeric species of ATP Synthase and anomalous mitochondrial morphologies in the form of onion-like structures. The mitochondrial ultrastructure at the cristae level is thus modified. Electron microscopy on cross-sections of wild type mitochondria display many short cristae with narrowed intra-cristae space, whereas yeast mutants defected in supramolecular ATP Synthases assembly present a low number of large lamellar cristae of constant thickness and traversing the whole organelle. The growth of these internal structures leads finally to mitochondria with sphere-like structures with a mean diameter of 1 μm that are easily identified by epifluorescence microscopy. As a result, ATP Synthase is an actor of the mitochondrial ultrastructure in yeast. This paper reviews the ATP Synthase components whose modifications lead to anomalous mitochondrial morphology and also provides a schema showing the formation of the so-called onion-like structures.

  • Supramolecular organization of the yeast F1Fo-ATP Synthase.
    Biology of the Cell, 2008
    Co-Authors: Daniel Thomas, Jean Velours, Alain Dautant, Benedicte Salin, Patrick Bron, Théodore Weimann, Marie-france Giraud, Patrick Paumard, Annie Cavalier, Daniel Brèthes

    Abstract:

    Background information. The yeast mitochondrial F1Fo-ATP Synthase is a large complex of 600 kDa that uses the proton electrochemical gradient generated by the respiratory chain to catalyse ATP synthesis from ADP and Pi. For a large range of organisms, it has been shown that mitochondrial ATP Synthase adopts oligomeric structures. Moreover, several studies have suggested that a link exists between ATP Synthase and mitochondrial morphology. Results and discussion. In order to understand the link between ATP Synthase oligomerization and mitochondrial morphology, more information is needed on the supramolecular organization of this enzyme within the inner mitochondrial membrane. We have conducted an electron microscopy study on wild-type yeast mitochondria at different levels of organization from spheroplast to isolated ATP Synthase complex. Using electron tomography, freeze-fracture, negative staining and image processing, we show that cristae form a network of lamellae, on which ATP Synthase dimers assemble in linear and regular arrays of oligomers. Conclusions. Our results shed new light on the supramolecular organization of the F1Fo-ATP Synthase and its potential role in mitochondrial morphology.

Valentina Giorgio – 3rd expert on this subject based on the ideXlab platform

  • The role of mitochondrial ATP Synthase in cancer.
    Biological chemistry, 2020
    Co-Authors: Chiara Galber, Manuel Jesus Acosta, Giovanni Minervini, Valentina Giorgio

    Abstract:

    The mitochondrial ATP Synthase is a multi-subunit enzyme complex located in the inner mitochondrial membrane which is essential for oxidative phosphorylation under physiological conditions. In this review, we analyse the enzyme functions involved in cancer progression by dissecting specific conditions in which ATP Synthase contributes to cancer development or metastasis. Moreover, we propose the role of ATP Synthase in the formation of the permeability transition pore (PTP) as an additional mechanism which controls tumour cell death. We further describe transcriptional and translational modifications of the enzyme subunits and of the inhibitor protein IF1that may promote adaptations leading to cancer metabolism. Finally, we outline ATP Synthase gene mutations and epigenetic modifications associated with cancer development or drug resistance, with the aim of highlighting this enzyme complex as a potential novel target for future anti-cancer therapy.

  • dimers of mitochondrial ATP Synthase form the permeability transition pore
    Proceedings of the National Academy of Sciences of the United States of America, 2013
    Co-Authors: Valentina Giorgio, Sophia Von Stockum, Manuela Antoniel, Astrid Fabbro, Federico Fogolari, Michael Forte, Gary D Glick, Valeria Petronilli, Mario Zoratti, Ildiko Szabo

    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.

  • cyclophilin d modulates mitochondrial f0f1 ATP Synthase by interacting with the lateral stalk of the complex
    Journal of Biological Chemistry, 2009
    Co-Authors: Valentina Giorgio, Michael Forte, Valeria Petronilli, Elena Bisetto, Maria Eugenia Soriano, Federica Dabbenisala, Emy Basso, Paolo Bernardi, Giovanna Lippe

    Abstract:

    Blue native gel electrophoresis purification and immunoprecipitation of F0F1-ATP Synthase from bovine heart mitochondria revealed that cyclophilin (CyP) D associates to the complex. Treatment of intact mitochondria with the membrane-permeable bifunctional reagent dimethyl 3,3-dithiobis-propionimidate (DTBP) cross-linked CyPD with the lateral stalk of ATP Synthase, whereas no interactions with F1 sector subunits, the ATP Synthase natural inhibitor protein IF1, and the ATP/ADP carrier were observed. The ATP Synthase-CyPD interactions have functional consequences on enzyme catalysis and are modulated by phosphate (increased CyPD binding and decreased enzyme activity) and cyclosporin (Cs) A (decreased CyPD binding and increased enzyme activity). Treatment of MgATP submitochondrial particles or intact mitochondria with CsA displaced CyPD from membranes and activated both hydrolysis and synthesis of ATP sustained by the enzyme. No effect of CsA was detected in CyPD-null mitochondria, which displayed a higher specific activity of the ATP Synthase than wild-type mitochondria. Modulation by CyPD binding appears to be independent of IF1, whose association to ATP Synthase was not affected by CsA treatment. These findings demonstrate that CyPD association to the lateral stalk of ATP Synthase modulates the activity of the complex.