Mutation m.3395A > G in MT-ND1 leads to variable pathologic manifestations

2020 ◽  
Vol 29 (6) ◽  
pp. 980-989
Author(s):  
Nicolás Gutiérrez Cortés ◽  
Claire Pertuiset ◽  
Elodie Dumon ◽  
Marine Börlin ◽  
Barbara Da Costa ◽  
...  
Keyword(s):  
Complex I ◽  
Mitochondrial Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Functional Study ◽  
Mtdna Mutation ◽  
Wide Range ◽  
Complex I Assembly ◽  
First Time ◽  
Do So

Abstract A non-synonymous mtDNA mutation, m.3395A > G, which changes tyrosine in position 30 to cysteine in p.MT-ND1, was found in several patients with a wide range of clinical phenotypes such as deafness, diabetes and cerebellar syndrome but no Leber’s hereditary optic neuropathy. Although this mutation has already been described, its pathogenicity has not been demonstrated. Here, it was found isolated for the first time, allowing a study to investigate its pathogenicity. To do so, we constructed cybrid cell lines and carried out a functional study to assess the possible consequences of the mutation on mitochondrial bioenergetics. Results obtained demonstrated that this mutation causes an important dysfunction of the mitochondrial respiratory chain with a decrease in both activity and quantity of complex I due to a diminution of p.MT-ND1 quantity. However, no subcomplexes were found in cybrids carrying the mutation, indicating that the quality of the complex I assembly is not affected. Moreover, based on the crystal structure of p.MT-ND1 and the data found in the literature, we propose a hypothesis for the mechanism of the degradation of p.MT-ND1. Our study provides new insights into the pathophysiology of mitochondrial diseases and in particular of MT-ND1 mutations.

Election Forecasts in 1984: How Accurate Were They?

1985 ◽  
Vol 18 (01) ◽  
pp. 53-62 ◽  
Author(s):  
Michael S. Lewis-Beck
Keyword(s):  
Presidential Candidate ◽  
High Quality ◽  
Election Forecasting ◽  
Personal Favorite ◽  
World Series ◽  
The Poor ◽  
Wide Range ◽  
The World ◽  
Do So

One autumn out of four, election forecasting surpasses baseball as America's national pastime. Then, everyone wants to know who will win, and everyone has a guess. Now, with the ballots carefully counted, forecasters await their awards. Below, I evaluate the quality of a wide range of 1984 presidential and congressional forecasts. The evaluation proceeds from nonscientific to scientific approaches, although this distinction is sometimes blurred. To lower the level of suspense, I should say that some forecasts turned out to be quite good. By way of conclusion, I offer a set of rules for selecting a high-quality forecasting instrument.Lucky GuessesMany popular election forecasting rules take advantage of chance, which has been working in their favor. Perhaps the most famous is the World Series forecast, which says, “If the American League wins the World Series, then the Republican presidential candidate will win.” This technique was accurate from 1952 to 1976, missed in 1980, but worked again in 1984 with the victory of the Detroit Tigers. A lesser known rule of this type, which is my personal favorite, is based on the Beaujolais wine harvest. Accordingly, “If the Beaujolais vintage looks bad, then the Republican will take the presidency.” This has held post-1960, and continues to do so with the poor 1984 crop (yielding a wine too light, with little color). There are other such rules that relate more directly to the candidates themselves and, in that sense, have more verisimilitude.

scholarly journals The Tardigrade Hypsibius Exemplaris as an Emerging Model to Study the Mitochondrial Alternative Oxidase at Animal Organismal Level

2020 ◽  
Author(s):  
Daria Grobys ◽  
Milena Roszkowska ◽  
Łukasz Kaczmarek ◽  
Wiesława Jarmuszkiewicz ◽  
Andonis Karachitos ◽  
...  
Keyword(s):  
Alternative Oxidase ◽  
Mitochondrial Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Whole Body ◽  
Intact Specimen ◽  
Complex Iv ◽  
Animal Physiology ◽  
The Impact ◽  
First Time

Abstract Background: Mitochondrial alternative oxidase (AOX) is suggested to be present in mitochondria of most invertebrates but not vertebrates. Independently of the reason concerning the enzyme occurrence in animal mitochondria, expression of AOX in human mitochondria is regarded as a potential therapeutic strategy in treatment of mitochondrial diseases caused by the mitochondrial respiratory chain (MRC) deficiency or blockage. Undoubtedly, development of AOX expression-based therapy requires explanation of AOX contribution to animal physiology. Till now the relevant data has been obtained mainly due to heterologous AOX expression in cells and animals that do not have natively expressed AOX. We think that application of animals natively expressing AOX could importantly contribute to the research and therapy development. Because the available genomic and transcriptomic data suggests the presence of functional AOX protein in mitochondria of the tardigrade Hypsibius exemplaris, we decided to investigate the possibility of the animal application as a model for AOX activity analysis at organismal level.Results: We observed that H. exemplaris tolerance to the blockage of the MRC complexes III and/or IV was diminished in the presence of AOX inhibitor and the inhibitor-sensitive respiration enabled the tardigrade respiration under condition of the blockage. Furthermore, although detection of H. exemplaris AOX at protein level and pronounced oxygraphic registration of its activity required the MRC complex III and/or IV blockage, the obtained data indicated that AOX clearly contributed to the animal functioning, also in the absence of the blockage. Conclusions: According to our best knowledge we demonstrated, for the first time, that AOX activity of small aquatic invertebrates, represented by the studied tardigrade species, can be monitored by measurement of intact specimen whole-body respiration. Furthermore, it was also possible to monitor the impact of the MRC complex IV blockage on AOX expression level and AOX inhibition in the absence of the blockage on animal functioning. Thus, H. exemplaris could be applied as a whole-animal model suitable to study activity and expression regulation of natively expressed animal AOX.

scholarly journals Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

2016 ◽  
Vol 113 (46) ◽  
pp. 13063-13068 ◽  
Author(s):  
Irene Lopez-Fabuel ◽  
Juliette Le Douce ◽  
Angela Logan ◽  
Andrew M. James ◽  
Gilles Bonvento ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Complex I ◽  
Structural Organization ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Complex I ◽  
Ros Production ◽  
Oxygen Species ◽  
Mitochondrial Complex ◽  
Mitochondrial Ros ◽  
Complex I Assembly

Neurons depend on oxidative phosphorylation for energy generation, whereas astrocytes do not, a distinctive feature that is essential for neurotransmission and neuronal survival. However, any link between these metabolic differences and the structural organization of the mitochondrial respiratory chain is unknown. Here, we investigated this issue and found that, in neurons, mitochondrial complex I is predominantly assembled into supercomplexes, whereas in astrocytes the abundance of free complex I is higher. The presence of free complex I in astrocytes correlates with the severalfold higher reactive oxygen species (ROS) production by astrocytes compared with neurons. Using a complexomics approach, we found that the complex I subunit NDUFS1 was more abundant in neurons than in astrocytes. Interestingly, NDUFS1 knockdown in neurons decreased the association of complex I into supercomplexes, leading to impaired oxygen consumption and increased mitochondrial ROS. Conversely, overexpression of NDUFS1 in astrocytes promoted complex I incorporation into supercomplexes, decreasing ROS. Thus, complex I assembly into supercomplexes regulates ROS production and may contribute to the bioenergetic differences between neurons and astrocytes.

scholarly journals GRIM-19 Is Essential for Maintenance of Mitochondrial Membrane Potential

2008 ◽  
Vol 19 (5) ◽  
pp. 1893-1902 ◽  
Author(s):  
Hao Lu ◽  
Xinmin Cao
Keyword(s):  
Cell Death ◽  
Complex I ◽  
Mitochondrial Membrane ◽  
Transmembrane Potential ◽  
Mitochondrial Respiratory Chain ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Mitochondrial Localization ◽  
N Terminus ◽  
Complex I Assembly

GRIM-19 was found to copurify with complex I of mitochondrial respiratory chain and subsequently was demonstrated to be involved in complex I assembly and activity. To further understand its function in complex I, we dissected its functional domains by generating a number of deletion, truncation, and point mutants. The mitochondrial localization sequences were located at the N-terminus. Strikingly, deletion of residues 70–80, 90–100, or the whole C-terminal region (70–144) led to a loss of mitochondrial transmembrane potential (ΔΨm). However, similar deletions of another two complex I subunits, NDUFA9 and NDUFS3, did not show such effect. We also found that deletion of the last 10 residues affected GRIM-19's ability to be assembled to complex I. We constructed a dominant-negative mutant containing the N-terminal 60 and the last C-terminal 10 residues, which could be assembled into complex I, but failed to maintain normal ΔΨm. Cells overexpressing this mutant did not spontaneously undergo cell death, but were sensitized to apoptosis induced by cell death agents. Our results demonstrate that GRIM-19 is required for electron transfer activity of complex I, and disruption of ΔΨm by GRIM-19 mutants enhances the cells' sensitivity to apoptotic stimuli.

scholarly journals Integrating transcriptome and proteome analysis to determine the lignin synthesis pathway involved in Panax notoginseng in fungal stress

2021 ◽  
Author(s):  
Qian Yang ◽  
Jianbin Li ◽  
Lin Xiao ◽  
Jiani Peng ◽  
Jialing Sun ◽  
...  
Keyword(s):  
Proteome Analysis ◽  
Panax Notoginseng ◽  
Defense Responses ◽  
Lignin Synthesis ◽  
New Information ◽  
Wide Range ◽  
Proteomics Technology ◽  
Challenging Environment ◽  
First Time

Abstract Background Plants are constantly threatened by various pathogens in a challenging environment. Altemaria panax Whetzel is a destructive pathogen that affects many plants, including Panax notoginseng, and significantly reduces the yield and product quality of Panax notoginseng. It is not clear how Panax notoginseng responds to pathogen infection.Methods Using the advanced advantages of transcriptome and proteomics technology, we studied the response of Panax notoginseng to Altemaria panax stress.Results Compared with the control, fungal infection caused significant changes in the Panax notoginseng transcriptome and proteome. Specifically, a total of 136,100 transcripts and 4,468 proteins were identified. The integration of transcriptome and proteome profiles revealed many candidate transcripts/proteins, which may be involved in lignin synthesis during the activation of defense responses by Panax notoginseng. Many genes and proteins are induced or inhibited by fungi. Among them, the expression levels of genes PAL, 4CL, COMT, CAD and POX in the lignin synthesis pathway are significantly increased, which indicates that the fungus activates the defense response of Panax notoginseng.Conclusions As far as we know, this is the first time that transcriptome and proteome analysis have been combined to study the response of Panax notoginseng to disease. This study provides a wide range of new information about the transcriptome, proteome and their correlation of Panax notoginseng in response to fungal stress. The analysis of this resource allows us to examine the mechanisms of transcription and protein diversification, which expands the knowledge of the complexities of the transcriptome and proteome in traditional Chinese medicines.

scholarly journals Stimulating the sir2-pgc-1α axis rescues exercise capacity and mitochondrial respiration in Drosophila tafazzin mutants.

2022 ◽  
Author(s):  
Deena Damschroder ◽  
Rubén Zapata-Pérez ◽  
Riekelt H. Houtkooper ◽  
Robert Wessells
Keyword(s):  
Exercise Capacity ◽  
Mitochondrial Respiration ◽  
Mitochondrial Diseases ◽  
Barth Syndrome ◽  
Exercise Intolerance ◽  
Nicotinamide Riboside ◽  
Beneficial Effects ◽  
Severe Exercise ◽  
First Time

Cardiolipin (CL) is a phospholipid required for proper mitochondrial function. Tafazzin remodels CL to create highly unsaturated fatty acid chains. However, when tafazzin is mutated, CL remodeling is impeded, leading to mitochondrial dysfunction and the disease Barth syndrome. Patients with Barth syndrome often have severe exercise intolerance, which negatively impacts their overall quality of life. Boosting NAD+ levels can improve symptoms of other mitochondrial diseases, but its effect in the context of Barth syndrome has not been examined. We demonstrate for the first time that nicotinamide riboside (NR) can rescue exercise tolerance and mitochondrial respiration in a Drosophila tafazzin mutant and that the beneficial effects are dependent on sir2 and pgc-1α . Overexpressing pgc-1α increased the total abundance of cardiolipin in mutants. In addition, muscles and neurons were identified as key targets for future therapies because sir2 or pgc-1α overexpression in either of these tissues is sufficient to restore the exercise capacity of Drosophila tafazzin mutants.

scholarly journals Five Entry Points of the Mitochondrially Encoded Subunits in Mammalian Complex I Assembly

2010 ◽  
Vol 30 (12) ◽  
pp. 3038-3047 ◽  
Author(s):  
Ester Perales-Clemente ◽  
Erika Fernández-Vizarra ◽  
Rebeca Acín-Pérez ◽  
Nieves Movilla ◽  
María Pilar Bayona-Bafaluy ◽  
...  
Keyword(s):  
Complex I ◽  
Mitochondrial Respiratory Chain ◽  
Mouse Cell ◽  
Assembly Process ◽  
Large Size ◽  
Assembly Pathway ◽  
Complex Process ◽  
Entry Points ◽  
Complex I Assembly

ABSTRACT Complex I (CI) is the largest enzyme of the mammalian mitochondrial respiratory chain. The biogenesis of the complex is a very complex process due to its large size and number of subunits (45 subunits). The situation is further complicated due to the fact that its subunits have a double genomic origin, as seven of them are encoded by the mitochondrial DNA. Understanding of the assembly process and characterization of the involved factors has advanced very much in the last years. However, until now, a key part of the process, that is, how and at which step the mitochondrially encoded CI subunits (ND subunits) are incorporated in the CI assembly process, was not known. Analyses of several mouse cell lines mutated for three ND subunits allowed us to determine the importance of each one for complex assembly/stability and that there are five different steps within the assembly pathway in which some mitochondrially encoded CI subunit is incorporated.

scholarly journals Arabidopsis thaliana alternative dehydrogenases: a potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Alessia Catania ◽  
Arcangela Iuso ◽  
Juliette Bouchereau ◽  
Laura S. Kremer ◽  
Marina Paviolo ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Complex I ◽  
Mitochondrial Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Sod Activity ◽  
Respiratory Chain Defect ◽  
Human Control ◽  
Initial Hypothesis ◽  
Therapeutic Tools

Abstract Background Complex I (CI or NADH:ubiquinone oxidoreductase) deficiency is the most frequent cause of mitochondrial respiratory chain defect. Successful attempts to rescue CI function by introducing an exogenous NADH dehydrogenase, such as the NDI1 from Saccharomyces cerevisiae (ScNDI1), have been reported although with drawbacks related to competition with CI. In contrast to ScNDI1, which is permanently active in yeast naturally devoid of CI, plant alternative NADH dehydrogenases (NDH-2) support the oxidation of NADH only when the CI is metabolically inactive and conceivably when the concentration of matrix NADH exceeds a certain threshold. We therefore explored the feasibility of CI rescue by NDH-2 from Arabidopsis thaliana (At) in human CI defective fibroblasts. Results We showed that, other than ScNDI1, two different NDH-2 (AtNDA2 and AtNDB4) targeted to the mitochondria were able to rescue CI deficiency and decrease oxidative stress as indicated by a normalization of SOD activity in human CI-defective fibroblasts. We further demonstrated that when expressed in human control fibroblasts, AtNDA2 shows an affinity for NADH oxidation similar to that of CI, thus competing with CI for the oxidation of NADH as opposed to our initial hypothesis. This competition reduced the amount of ATP produced per oxygen atom reduced to water by half in control cells. Conclusions In conclusion, despite their promising potential to rescue CI defects, due to a possible competition with remaining CI activity, plant NDH-2 should be regarded with caution as potential therapeutic tools for human mitochondrial diseases.

LVLRF: Sistema de gestión de niveles de potencia de transmisión de señal CATV [LVLRF: management system of transmission power levels of CATV signal]

2010 ◽  
Author(s):  
Michael Alejandro Rojas Giraldo ◽  
Luis Carlos Correa Ortiz
Keyword(s):  
Cable Television ◽  
Transmission Power ◽  
Cable Tv ◽  
Wide Range ◽  
Rf Signals ◽  
Different Types ◽  
La Red ◽  
Monitoring Software ◽  
Do So

Resumen En la actualidad la televisión por cable es prácticamente una necesidad que envuelve a cada una de las personas y hogares del mundo, debido a su gran variedad de contenidos de diferentes tipos, los cuales se adaptan a los gustos de cada individuo. Este proyecto pretende brindar herramientas para que las empresas de telecomunicaciones prestadoras de este tipo de servicio, puedan hacerlo con calidad. Con base en lo anterior, se ha concebido este proyecto como una solución al problema del monitoreo de los niveles de las señales de RF en el origen de los sistemas de televisión por cable, debido a que si el origen de la señal varía 1 dBm, en la red el cambio sería de entre 4 y 6 dBm, lo cual se representa como una deficiencia en la calidad de la señal. Este proyecto está basado en un circuito detector de RF el cual entrega una lectura, que es procesada por un circuito de interconexión encargado de entregarla a cualquier conexión IP, de allí es recibida por un software de monitoreo que representará gráficamente todos los datos. Palabras ClaveTelevisión por Cable, monitoreo, radiofrecuencia, nivel de señal de radiofrecuencia.   Abstract Today cable television is almost a necessity that involves each of the individuals and households worldwide, due to its wide range of content of different types, which were adapted to the tastes of each individual. This project aims to provide tools for the telecommunications providers of such service may do so with quality. Based on the foregoing, this project has been conceived as a solution to the problem of monitoring the levels of RF signals in the origin of the cable television systems, because if the source of the signal varies a dBm, change in the network would be between 4 and 6 dBm, which is represented as a deficiency in the quality of the signal. This project is based on an RF detector circuit which provides a reading which is processed by a circuit interconnection charge to deliver it to any IP connection, there is received by monitoring software that plotted all the data. Keywords Cable TV, monitoring, radiofrequency, radiofrequency signal level.

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