The Experts below are selected from a list of 31305 Experts worldwide ranked by ideXlab platform
Vilma Kaplanová - One of the best experts on this subject based on the ideXlab platform.
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TMEM70 mutations cause isolated ATP Synthase deficiency and neonatal mitochondrial encephalocardiomyopathy
Nature Genetics, 2008Co-Authors: Alena Čížková, Viktor Stránecký, Johannes A Mayr, Markéta Tesařová, Vendula Havlíčková, Jan Paul, Robert Ivánek, Andreas W Kuss, Hana Hansíková, Vilma KaplanováAbstract: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.
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tmem70 mutations cause isolated ATP Synthase deficiency and neonatal mitochondrial encephalocardiomyopathy
Nature Genetics, 2008Co-Authors: Alena Cizkova, Viktor Stránecký, Johannes A Mayr, Vendula Havlíčková, Jan Paul, Robert Ivánek, Andreas W Kuss, Hana Hansíková, Marketa Tesarova, Vilma KaplanováAbstract: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 - One of the best experts on this subject based on the ideXlab platform.
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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, 2011Co-Authors: Jean Velours, Alain Dautant, Claire Stines-chaumeil, Johan Habersetzer, Stéphane Chaignepain, Daniel BrèthesAbstract: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.
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mitochondrial f1f0 ATP Synthase and organellar internal architecture
The International Journal of Biochemistry & Cell Biology, 2009Co-Authors: Jean Velours, Benedicte Salin, Alain Dautant, Isabelle Sagot, Daniel BrèthesAbstract: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.
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Supramolecular organization of the yeast F1Fo-ATP Synthase.
Biology of the Cell, 2008Co-Authors: Daniel Thomas, Jean Velours, Benedicte Salin, Alain Dautant, Patrick Bron, Théodore Weimann, Marie-france Giraud, Patrick Paumard, Annie Cavalier, Daniel BrèthesAbstract: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.
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Characterization of Domain Interfaces in Monomeric and Dimeric ATP Synthase
Molecular & Cellular Proteomics, 2008Co-Authors: Ilka Wittig, Jean Velours, Rosemary A. Stuart, Hermann SchäggerAbstract:: We disassembled monomeric and dimeric yeast ATP Synthase under mild conditions to identify labile proteins and transiently stable subcomplexes that had not been observed before. Specific removal of subunits alpha, beta, oligomycin sensitivity conferring protein (OSCP), and h disrupted the ATP Synthase at the gamma-alpha(3)beta(3) rotor-stator interface. Loss of two F(1)-parts from dimeric ATP Synthase led to the isolation of a dimeric subcomplex containing membrane and peripheral stalk proteins thus identifying the membrane/peripheral stalk sectors immediately as the dimerizing parts of ATP Synthase. Almost all subunit a was found associated with a ring of 10 c-subunits in two-dimensional blue native/SDS gels. We therefore postulate that c10a1-complex is a stable structure in resting ATP Synthase until the entry of protons induces a breaking of interactions and stepwise rotation of the c-ring relative to the a-subunit in the catalytic mechanism. Dimeric subunit a was identified in SDS gels in association with two c10-rings suggesting that a c10a2c10-complex may constitute an important part of the monomer-monomer interface in dimeric ATP Synthase that seems to be further tightened by subunits b, i, e, g, and h. In contrast to the monomer-monomer interface, the interface between dimers in higher oligomeric structures remains largely unknown. However, we could show that the natural inhibitor protein Inh1 is not required for oligomerization.
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the ATP Synthase is involved in generating mitochondrial cristae morphology
The EMBO Journal, 2002Co-Authors: Patrick Paumard, Daniel Brèthes, Jacques Vaillier, Benedicte Coulary, Jacques Schaeffer, Vincent Soubannier, David M Mueller, Jeanpaul Di Rago, Jean VeloursAbstract:The inner membrane of the mitochondrion folds inwards, forming the cristae. This folding allows a greater amount of membrane to be packed into the mitochondrion. The data in this study demonstrate that subunits e and g of the mitochondrial ATP Synthase are involved in generating mitochondrial cristae morphology. These two subunits are non‐essential components of ATP Synthase and are required for the dimerization and oligomerization of ATP Synthase. Mitochondria of yeast cells deficient in either subunits e or g were found to have numerous digitations and onion‐like structures that correspond to an uncontrolled biogenesis and/or folding of the inner mitochondrial membrane. The present data show that there is a link between dimerization of the mitochondrial ATP Synthase and cristae morphology. A model is proposed of the assembly of ATP Synthase dimers, taking into account the oligomerization of the yeast enzyme and earlier data on the ultrastructure of mitochondrial cristae, which suggests that the association of ATP Synthase dimers is involved in the control of the biogenesis of the inner mitochondrial membrane.
Valentina Giorgio - One of the best experts on this subject based on the ideXlab platform.
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The role of mitochondrial ATP Synthase in cancer.
Biological chemistry, 2020Co-Authors: Chiara Galber, Manuel Jesus Acosta, Giovanni Minervini, Valentina GiorgioAbstract: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.
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dimers of mitochondrial ATP Synthase form the permeability transition pore
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Valentina Giorgio, Sophia Von Stockum, Manuela Antoniel, Astrid Fabbro, Federico Fogolari, Michael Forte, Gary D Glick, Valeria Petronilli, Mario Zoratti, Ildiko SzaboAbstract: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.
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cyclophilin d modulates mitochondrial f0f1 ATP Synthase by interacting with the lateral stalk of the complex
Journal of Biological Chemistry, 2009Co-Authors: Valentina Giorgio, Michael Forte, Valeria Petronilli, Elena Bisetto, Maria Eugenia Soriano, Federica Dabbenisala, Emy Basso, Paolo Bernardi, Giovanna LippeAbstract: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.
Daniel Brèthes - One of the best experts on this subject based on the ideXlab platform.
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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, 2011Co-Authors: Jean Velours, Alain Dautant, Claire Stines-chaumeil, Johan Habersetzer, Stéphane Chaignepain, Daniel BrèthesAbstract: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.
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mitochondrial f1f0 ATP Synthase and organellar internal architecture
The International Journal of Biochemistry & Cell Biology, 2009Co-Authors: Jean Velours, Benedicte Salin, Alain Dautant, Isabelle Sagot, Daniel BrèthesAbstract: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.
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Supramolecular organization of the yeast F1Fo-ATP Synthase.
Biology of the Cell, 2008Co-Authors: Daniel Thomas, Jean Velours, Benedicte Salin, Alain Dautant, Patrick Bron, Théodore Weimann, Marie-france Giraud, Patrick Paumard, Annie Cavalier, Daniel BrèthesAbstract: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.
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the ATP Synthase is involved in generating mitochondrial cristae morphology
The EMBO Journal, 2002Co-Authors: Patrick Paumard, Daniel Brèthes, Jacques Vaillier, Benedicte Coulary, Jacques Schaeffer, Vincent Soubannier, David M Mueller, Jeanpaul Di Rago, Jean VeloursAbstract:The inner membrane of the mitochondrion folds inwards, forming the cristae. This folding allows a greater amount of membrane to be packed into the mitochondrion. The data in this study demonstrate that subunits e and g of the mitochondrial ATP Synthase are involved in generating mitochondrial cristae morphology. These two subunits are non‐essential components of ATP Synthase and are required for the dimerization and oligomerization of ATP Synthase. Mitochondria of yeast cells deficient in either subunits e or g were found to have numerous digitations and onion‐like structures that correspond to an uncontrolled biogenesis and/or folding of the inner mitochondrial membrane. The present data show that there is a link between dimerization of the mitochondrial ATP Synthase and cristae morphology. A model is proposed of the assembly of ATP Synthase dimers, taking into account the oligomerization of the yeast enzyme and earlier data on the ultrastructure of mitochondrial cristae, which suggests that the association of ATP Synthase dimers is involved in the control of the biogenesis of the inner mitochondrial membrane.
Alain Dautant - One of the best experts on this subject based on the ideXlab platform.
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ATP Synthase diseases of mitochondrial genetic origin
Frontiers in Physiology, 2018Co-Authors: Alain Dautant, Jeanpaul Di Rago, Thomas Meier, Alexander Hahn, Deborah Tribouillardtanvier, Roza KucharczykAbstract:Devastating human neuromuscular disorders have been associated to defects in the ATP Synthase. This enzyme is found in the inner mitochondrial membrane and catalyzes the last step in oxidative phosphorylation, which provides aerobic eukaryotes with ATP. With the advent of structures of complete ATP Synthases, and the availability of genetically approachable systems such as the yeast Saccharomyces cerevisiae, we can begin to understand these molecular machines and their associated defects at the molecular level. In this review, we describe what is known about the clinical syndromes induced by 58 different mutations found in the mitochondrial genes encoding membrane subunits 8 and a of ATP Synthase, and evaluate their functional consequences with respect to recently described cryo-EM structures of this enzyme.
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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, 2011Co-Authors: Jean Velours, Alain Dautant, Claire Stines-chaumeil, Johan Habersetzer, Stéphane Chaignepain, Daniel BrèthesAbstract: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.
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mitochondrial f1f0 ATP Synthase and organellar internal architecture
The International Journal of Biochemistry & Cell Biology, 2009Co-Authors: Jean Velours, Benedicte Salin, Alain Dautant, Isabelle Sagot, Daniel BrèthesAbstract: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.
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Supramolecular organization of the yeast F1Fo-ATP Synthase.
Biology of the Cell, 2008Co-Authors: Daniel Thomas, Jean Velours, Benedicte Salin, Alain Dautant, Patrick Bron, Théodore Weimann, Marie-france Giraud, Patrick Paumard, Annie Cavalier, Daniel BrèthesAbstract: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.
