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Article ; Online: Targeting Copper Homeostasis Improves Functioning of

Soczewka, Piotr / Tribouillard-Tanvier, Déborah / di Rago, Jean-Paul / Zoladek, Teresa / Kaminska, Joanna

International journal of molecular sciences

2021 Volume 22, Issue 5

Abstract: Ion homeostasis is crucial for organism functioning, and its alterations may cause diseases. For example, copper insufficiency and overload are associated with Menkes and Wilson's diseases, respectively, and iron imbalance is observed in Parkinson's and ... ...

Abstract	Ion homeostasis is crucial for organism functioning, and its alterations may cause diseases. For example, copper insufficiency and overload are associated with Menkes and Wilson's diseases, respectively, and iron imbalance is observed in Parkinson's and Alzheimer's diseases. To better understand human diseases,
MeSH term(s)	Copper/pharmacology ; Copper Transport Proteins/genetics ; Copper Transport Proteins/metabolism ; Gene Expression Regulation/drug effects ; Homeostasis ; Humans ; Mutation ; Saccharomyces cerevisiae/drug effects ; Saccharomyces cerevisiae/growth & development ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
Chemical Substances	Copper Transport Proteins ; Saccharomyces cerevisiae Proteins ; VPS13 protein, S cerevisiae ; Copper (789U1901C5)
Language	English
Publishing date	2021-02-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22052248
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Article ; Online: Molecular basis of diseases induced by the mitochondrial DNA mutation m.9032T>C.

Baranowska, Emilia / Niedzwiecka, Katarzyna / Panja, Chiranjit / Charles, Camille / Dautant, Alain / di Rago, Jean-Paul / Tribouillard-Tanvier, Déborah / Kucharczyk, Roza

Human molecular genetics

2022 Volume 32, Issue 8, Page(s) 1313–1323

Abstract: The mitochondrial DNA mutation m.9032T>C was previously identified in patients presenting with NARP (Neuropathy Ataxia Retinitis Pigmentosa). Their clinical features had a maternal transmission and patient's cells showed a reduced oxidative ... ...

Abstract	The mitochondrial DNA mutation m.9032T>C was previously identified in patients presenting with NARP (Neuropathy Ataxia Retinitis Pigmentosa). Their clinical features had a maternal transmission and patient's cells showed a reduced oxidative phosphorylation capacity, elevated reactive oxygen species (ROS) production and hyperpolarization of the mitochondrial inner membrane, providing evidence that m.9032T>C is truly pathogenic. This mutation leads to replacement of a highly conserved leucine residue with proline at position 169 of ATP synthase subunit a (L169P). This protein and a ring of identical c-subunits (c-ring) move protons through the mitochondrial inner membrane coupled to ATP synthesis. We herein investigated the consequences of m.9032T>C on ATP synthase in a strain of Saccharomyces cerevisiae with an equivalent mutation (L186P). The mutant enzyme assembled correctly but was mostly inactive as evidenced by a > 95% drop in the rate of mitochondrial ATP synthesis and absence of significant ATP-driven proton pumping across the mitochondrial membrane. Intragenic suppressors selected from L186P yeast restoring ATP synthase function to varying degrees (30-70%) were identified at the original mutation site (L186S) or in another position of the subunit a (H114Q, I118T). In light of atomic structures of yeast ATP synthase recently described, we conclude from these results that m.9032T>C disrupts proton conduction between the external side of the membrane and the c-ring, and that H114Q and I118T enable protons to access the c-ring through a modified pathway.
MeSH term(s)	Humans ; Saccharomyces cerevisiae/genetics ; Protons ; Mitochondrial Proton-Translocating ATPases/genetics ; Adenosine Triphosphate/metabolism ; Mutation ; DNA, Mitochondrial/genetics
Chemical Substances	Protons ; Mitochondrial Proton-Translocating ATPases (EC 3.6.3.-) ; Adenosine Triphosphate (8L70Q75FXE) ; DNA, Mitochondrial
Language	English
Publishing date	2022-11-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddac292
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Article ; Online: Creation of Yeast Models for Evaluating the Pathogenicity of Mutations in the Human Mitochondrial Gene MT-ATP6 and Discovering Therapeutic Molecules.

Tribouillard-Tanvier, Déborah / Dautant, Alain / Godard, François / Charles, Camille / Panja, Chiranjit / di Rago, Jean-Paul / Kucharczyk, Roza

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2497, Page(s) 221–242

Abstract: Numerous diseases in humans have been associated with mutations of the mitochondrial genome (mtDNA). This genome encodes 13 protein subunits of complexes involved in oxidative phosphorylation (OXPHOS), a process that provides aerobic eukaryotes with the ... ...

Abstract	Numerous diseases in humans have been associated with mutations of the mitochondrial genome (mtDNA). This genome encodes 13 protein subunits of complexes involved in oxidative phosphorylation (OXPHOS), a process that provides aerobic eukaryotes with the energy-rich adenosine triphosphate molecule (ATP). Mutations of the mtDNA may therefore have dramatic consequences especially in tissues and organs with high energy demand. Evaluating the pathogenicity of these mutations may be difficult because they often affect only a fraction of the numerous copies of the mitochondrial genome (up to several thousands in a single cell), which is referred to as heteroplasmy. Furthermore, due to its exposure to reactive oxygen species (ROS) produced in mitochondria, the mtDNA is prone to mutations, and some may be simply neutral polymorphisms with no detrimental consequences on human health. Another difficulty is the absence of methods for genetically transforming human mitochondria. Face to these complexities, the yeast Saccharomyces cerevisiae provides a convenient model for investigating the consequences of human mtDNA mutations in a defined genetic background. Owing to its good fermentation capacity, it can survive the loss of OXPHOS, its mitochondrial genome can be manipulated, and genetic heterogeneity in its mitochondria is unstable. Taking advantage of these unique attributes, we herein describe a method we have developed for creating yeast models of mitochondrial ATP6 gene mutations detected in patients, to determine how they impact OXPHOS. Additionally, we describe how these models can be used to discover molecules with therapeutic potential.
MeSH term(s)	DNA, Mitochondrial/genetics ; DNA, Mitochondrial/metabolism ; Genes, Mitochondrial ; Humans ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondrial Proton-Translocating ATPases/genetics ; Mitochondrial Proton-Translocating ATPases/metabolism ; Mutation ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Virulence
Chemical Substances	ATP6 protein, S cerevisiae ; DNA, Mitochondrial ; MT-ATP6 protein, human ; Saccharomyces cerevisiae Proteins ; Mitochondrial Proton-Translocating ATPases (EC 3.6.3.-)
Language	English
Publishing date	2022-06-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2309-1_14
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Article ; Online: Targeting Copper Homeostasis Improves Functioning of vps13 Δ Yeast Mutant Cells, a Model of VPS13 -Related Diseases

Piotr Soczewka / Déborah Tribouillard-Tanvier / Jean-Paul di Rago / Teresa Zoladek / Joanna Kaminska

International Journal of Molecular Sciences, Vol 22, Iss 5, p

2021 Volume 2248

Abstract: Ion homeostasis is crucial for organism functioning, and its alterations may cause diseases. For example, copper insufficiency and overload are associated with Menkes and Wilson’s diseases, respectively, and iron imbalance is observed in Parkinson’s and ... ...

Abstract	Ion homeostasis is crucial for organism functioning, and its alterations may cause diseases. For example, copper insufficiency and overload are associated with Menkes and Wilson’s diseases, respectively, and iron imbalance is observed in Parkinson’s and Alzheimer’s diseases. To better understand human diseases, Saccharomyces cerevisiae yeast are used as a model organism. In our studies, we used the vps13 Δ yeast strain as a model of rare neurological diseases caused by mutations in VPS13A – D genes. In this work, we show that overexpression of genes encoding copper transporters, CTR1 , CTR3 , and CCC2 , or the addition of copper salt to the medium, improved functioning of the vps13 Δ mutant. We show that their mechanism of action, at least partially, depends on increasing iron content in the cells by the copper-dependent iron uptake system. Finally, we present that treatment with copper ionophores, disulfiram, elesclomol, and sodium pyrithione, also resulted in alleviation of the defects observed in vps13 Δ cells. Our study points at copper and iron homeostasis as a potential therapeutic target for further investigation in higher eukaryotic models of VPS13 -related diseases.
Keywords	yeast model ; neurodegeneration ; VPS13 ; CTR1 ; CCC2 ; FET3 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Probing the pathogenicity of patient-derived variants of MT-ATP6 in yeast.

Baranowska, Emilia / Niedzwiecka, Katarzyna / Panja, Chiranjit / Charles, Camille / Dautant, Alain / Poznanski, Jarosław / di Rago, Jean-Paul / Tribouillard-Tanvier, Déborah / Kucharczyk, Roza

Disease models & mechanisms

2023 Volume 16, Issue 4

Abstract: The list of mitochondrial DNA (mtDNA) variants detected in individuals with neurodegenerative diseases is constantly growing. Evaluating their functional consequences and pathogenicity is not easy, especially when they are found in only a limited number ... ...

Abstract	The list of mitochondrial DNA (mtDNA) variants detected in individuals with neurodegenerative diseases is constantly growing. Evaluating their functional consequences and pathogenicity is not easy, especially when they are found in only a limited number of patients together with wild-type mtDNA (heteroplasmy). Owing to its amenability to mitochondrial genetic transformation and incapacity to stably maintain heteroplasmy, and the strong evolutionary conservation of the proteins encoded in mitochondria, Saccharomyces cerevisiae provides a convenient model to investigate the functional consequences of human mtDNA variants. We herein report the construction and energy-transducing properties of yeast models of eight MT-ATP6 gene variants identified in patients with various disorders: m.8843T>C, m.8950G>A, m.9016A>G, m.9025G>A, m.9029A>G, m.9058A>G, m.9139G>A and m.9160T>C. Significant defect in growth dependent on respiration and deficits in ATP production were observed in yeast models of m.8950G>A, m.9025G>A and m.9029A>G, providing evidence of pathogenicity for these variants. Yeast models of the five other variants showed very mild, if any, effect on mitochondrial function, suggesting that the variants do not have, at least alone, the potential to compromise human health.
MeSH term(s)	Humans ; DNA, Mitochondrial/genetics ; DNA, Mitochondrial/metabolism ; Mitochondria/metabolism ; Mitochondrial Proton-Translocating ATPases/genetics ; Mitochondrial Proton-Translocating ATPases/metabolism ; Mutation/genetics ; Saccharomyces cerevisiae/metabolism ; Virulence
Chemical Substances	DNA, Mitochondrial ; Mitochondrial Proton-Translocating ATPases (EC 3.6.3.-) ; MT-ATP6 protein, human
Language	English
Publishing date	2023-04-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.049783
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Article ; Online: Functional mapping of N-terminal residues in the yeast proteome uncovers novel determinants for mitochondrial protein import.

Nashed, Salomé / El Barbry, Houssam / Benchouaia, Médine / Dijoux-Maréchal, Angélie / Delaveau, Thierry / Ruiz-Gutierrez, Nadia / Gaulier, Lucie / Tribouillard-Tanvier, Déborah / Chevreux, Guillaume / Le Crom, Stéphane / Palancade, Benoit / Devaux, Frédéric / Laine, Elodie / Garcia, Mathilde

PLoS genetics

2023 Volume 19, Issue 8, Page(s) e1010848

Abstract: N-terminal ends of polypeptides are critical for the selective co-translational recruitment of N-terminal modification enzymes. However, it is unknown whether specific N-terminal signatures differentially regulate protein fate according to their cellular ...

Abstract	N-terminal ends of polypeptides are critical for the selective co-translational recruitment of N-terminal modification enzymes. However, it is unknown whether specific N-terminal signatures differentially regulate protein fate according to their cellular functions. In this work, we developed an in-silico approach to detect functional preferences in cellular N-terminomes, and identified in S. cerevisiae more than 200 Gene Ontology terms with specific N-terminal signatures. In particular, we discovered that Mitochondrial Targeting Sequences (MTS) show a strong and specific over-representation at position 2 of hydrophobic residues known to define potential substrates of the N-terminal acetyltransferase NatC. We validated mitochondrial precursors as co-translational targets of NatC by selective purification of translating ribosomes, and found that their N-terminal signature is conserved in Saccharomycotina yeasts. Finally, systematic mutagenesis of the position 2 in a prototypal yeast mitochondrial protein confirmed its critical role in mitochondrial protein import. Our work highlights the hydrophobicity of MTS N-terminal residues and their targeting by NatC as important features for the definition of the mitochondrial proteome, providing a molecular explanation for mitochondrial defects observed in yeast or human NatC-depleted cells. Functional mapping of N-terminal residues thus has the potential to support the discovery of novel mechanisms of protein regulation or targeting.
MeSH term(s)	Humans ; Saccharomyces cerevisiae/genetics ; Amino Acid Sequence ; Proteome/metabolism ; Protein Transport ; Fungal Proteins/metabolism ; Mitochondrial Proteins/metabolism
Chemical Substances	Proteome ; Fungal Proteins ; Mitochondrial Proteins
Language	English
Publishing date	2023-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010848
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Article ; Online: Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial

Su, Xin / Dautant, Alain / Godard, François / Bouhier, Marine / Zoladek, Teresa / Kucharczyk, Roza / di Rago, Jean-Paul / Tribouillard-Tanvier, Déborah

International journal of molecular sciences

2020 Volume 21, Issue 14

Abstract: Probing the pathogenicity and functional consequences of mitochondrial DNA (mtDNA) mutations from patient's cells and tissues is difficult due to genetic heteroplasmy (co-existence of wild type and mutated mtDNA in cells), occurrence of numerous mtDNA ... ...

Abstract	Probing the pathogenicity and functional consequences of mitochondrial DNA (mtDNA) mutations from patient's cells and tissues is difficult due to genetic heteroplasmy (co-existence of wild type and mutated mtDNA in cells), occurrence of numerous mtDNA polymorphisms, and absence of methods for genetically transforming human mitochondria. Owing to its good fermenting capacity that enables survival to loss-of-function mtDNA mutations, its amenability to mitochondrial genome manipulation, and lack of heteroplasmy,
MeSH term(s)	Adenosine Triphosphate/metabolism ; DNA, Mitochondrial/genetics ; Membrane Potential, Mitochondrial/genetics ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondrial Proton-Translocating ATPases/chemistry ; Mitochondrial Proton-Translocating ATPases/genetics ; Mitochondrial Proton-Translocating ATPases/metabolism ; Models, Chemical ; Mutation ; Oxidative Phosphorylation ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
Chemical Substances	ATP6 protein, S cerevisiae ; DNA, Mitochondrial ; Saccharomyces cerevisiae Proteins ; Adenosine Triphosphate (8L70Q75FXE) ; Mitochondrial Proton-Translocating ATPases (EC 3.6.3.-)
Language	English
Publishing date	2020-07-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21145083
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Article ; Online: Flavonoids as Potential Drugs for

Soczewka, Piotr / Flis, Krzysztof / Tribouillard-Tanvier, Déborah / di Rago, Jean-Paul / Santos, Cláudia N / Menezes, Regina / Kaminska, Joanna / Zoladek, Teresa

Genes

2020 Volume 11, Issue 7

Abstract: Several rare neurodegenerative diseases, including chorea acanthocytosis, are caused by mutations in ... ...

Abstract	Several rare neurodegenerative diseases, including chorea acanthocytosis, are caused by mutations in the
MeSH term(s)	Biological Products/chemistry ; Biological Products/pharmacology ; Cell Proliferation/drug effects ; Copper Transport Proteins/genetics ; Copper Transport Proteins/metabolism ; Drug Discovery/methods ; High-Throughput Screening Assays/methods ; Iron/metabolism ; Iron-Binding Proteins/genetics ; Iron-Binding Proteins/metabolism ; Luteolin/chemistry ; Luteolin/pharmacology ; Neuroprotective Agents/chemistry ; Neuroprotective Agents/pharmacology ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Structure-Activity Relationship ; Suppression, Genetic
Chemical Substances	Biological Products ; Copper Transport Proteins ; FET4 protein, S cerevisiae ; Iron-Binding Proteins ; Neuroprotective Agents ; Saccharomyces cerevisiae Proteins ; Small Molecule Libraries ; VPS13 protein, S cerevisiae ; Iron (E1UOL152H7) ; Luteolin (KUX1ZNC9J2)
Language	English
Publishing date	2020-07-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes11070828
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Article ; Online: Functional investigation of an universally conserved leucine residue in subunit a of ATP synthase targeted by the pathogenic m.9176 T>G mutation.

Kucharczyk, Roza / Dautant, Alain / Godard, François / Tribouillard-Tanvier, Déborah / di Rago, Jean-Paul

Biochimica et biophysica acta. Bioenergetics

2018 Volume 1860, Issue 1, Page(s) 52–59

Abstract: Protons are transported from the mitochondrial matrix to the intermembrane space of mitochondria during the transfer of electrons to oxygen and shuttled back to the matrix by the a subunit and a ring of identical c subunits across the membrane domain ( ... ...

Abstract	Protons are transported from the mitochondrial matrix to the intermembrane space of mitochondria during the transfer of electrons to oxygen and shuttled back to the matrix by the a subunit and a ring of identical c subunits across the membrane domain (F
MeSH term(s)	Adenosine Triphosphate/biosynthesis ; Conserved Sequence ; Humans ; Leigh Disease/etiology ; Leucine/physiology ; Mitochondrial Myopathies/etiology ; Mitochondrial Proton-Translocating ATPases/chemistry ; Mitochondrial Proton-Translocating ATPases/genetics ; Mutation ; Protein Subunits ; Retinitis Pigmentosa/etiology ; Saccharomyces cerevisiae Proteins/genetics ; Structure-Activity Relationship
Chemical Substances	ATP6 protein, S cerevisiae ; Protein Subunits ; Saccharomyces cerevisiae Proteins ; Adenosine Triphosphate (8L70Q75FXE) ; Mitochondrial Proton-Translocating ATPases (EC 3.6.3.-) ; Leucine (GMW67QNF9C)
Language	English
Publishing date	2018-11-07
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2650 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2650 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbabio.2018.11.005
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Article: Functional investigation of an universally conserved leucine residue in subunit a of ATP synthase targeted by the pathogenic m.9176 T>G mutation

Kucharczyk, Roza / Alain Dautant / François Godard / Déborah Tribouillard-Tanvier / Jean-Paul di Rago

Biochimica et biophysica acta. 2019 Jan., v. 1860, no. 1

2019

Abstract	Protons are transported from the mitochondrial matrix to the intermembrane space of mitochondria during the transfer of electrons to oxygen and shuttled back to the matrix by the a subunit and a ring of identical c subunits across the membrane domain (FO) of ATP synthase, which is coupled to ATP synthesis. A mutation (m.9176 T > G) of the mitochondrial ATP6 gene that replaces an universally conserved leucine residue into arginine at amino acid position 217 of human subunit a (aL217R) has been associated to NARP (Neuropathy, Ataxia and Retinitis Pigmentosa) and MILS (Maternally Inherited Leigh's Syndrome) diseases. We previously showed that an equivalent thereof in Saccharomyces cerevisiae (aL237R) severely impairs subunit a assembly/stability and decreases by >90% the rate of mitochondrial ATP synthesis. Herein we identified three spontaneous first-site intragenic suppressors (aR237M, aR237T and aR237S) that fully restore ATP synthase assembly. However, mitochondrial ATP synthesis rate was only partially recovered (40–50% vs wild type yeast). In light of recently described high-resolution yeast ATP synthase structures, the detrimental consequences of the aL237R change can be explained by steric and electrostatic hindrance with the universally conserved subunit a arginine residue (aR176) that is essential to FO activity. aL237 together with three other nearby hydrophobic residues have been proposed to prevent ion shortage between two physically separated hydrophilic pockets within the FO. Our results suggest that aL237 favors subunit c-ring rotation by optimizing electrostatic interaction between aR176 and an acidic residue in subunit c (cE59) known to be essential also to the activity of FO.
Keywords	H+/K+-exchanging ATPase ; H-transporting ATP synthase ; Saccharomyces cerevisiae ; adenosine triphosphate ; arginine ; electrons ; electrostatic interactions ; genes ; humans ; hydrophilicity ; hydrophobicity ; inheritance (genetics) ; leucine ; mitochondria ; mutation ; oxygen ; peripheral nervous system diseases ; protons ; retinitis pigmentosa ; yeasts
Language	English
Dates of publication	2019-01
Size	p. 52-59.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	282711-6
ISSN	0005-2728 ; 0304-4173
ISSN	0005-2728 ; 0304-4173
DOI	10.1016/j.bbabio.2018.11.005
Database	NAL-Catalogue (AGRICOLA)

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