scholarly journals Novel MTND1 mutations cause isolated exercise intolerance, complex I deficiency and increased assembly factor expression

2015 ◽  
Vol 128 (12) ◽  
pp. 895-904 ◽  
Author(s):  
Grainne S. Gorman ◽  
Emma L. Blakely ◽  
Hue-Tran Hornig-Do ◽  
Helen A.L. Tuppen ◽  
Laura C. Greaves ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Complex I ◽  
Nadh Dehydrogenase ◽  
Gene Mutations ◽  
Exercise Intolerance ◽  
Nadh Dehydrogenase Subunit ◽  
Gene Encoding ◽  
Compensatory Response ◽  
Catalytic Core ◽  
Assembly Factor

Complex I (CI) is the largest of the five multi-subunit complexes constituting the human oxidative phosphorylation (OXPHOS) system. Seven of its catalytic core subunits are encoded by mitochondrial DNA (ND (NADH dehydrogenase)1–6, ND4L (NADH dehydrogenase subunit 4L)), with mutations in all seven having been reported in association with isolated CI deficiency. We investigated two unrelated adult patients presenting with marked exercise intolerance, persistent lactic acidaemia and severe muscle-restricted isolated CI deficiency associated with sub-sarcolemmal mitochondrial accumulation. Screening of the mitochondrial genome detected novel mutations in the MTND1 (NADH dehydrogenase subunit 1) gene, encoding subunit of CI [Patient 1, m.3365T>C predicting p.(Leu20Pro); Patient 2, m.4175G>A predicting p.(Trp290*)] at high levels of mitochondrial DNA heteroplasmy in skeletal muscle. We evaluated the effect of these novel MTND1 mutations on complex assembly showing that CI assembly, although markedly reduced, was viable in the absence of detectable ND1 signal. Real-time PCR and Western blotting showed overexpression of different CI assembly factor transcripts and proteins in patient tissue. Together, our data indicate that the mechanism underlying the expression of the biochemical defect may involve a compensatory response to the novel MTND1 gene mutations, promoting assembly factor up-regulation and stabilization of respiratory chain super-complexes, resulting in partial rescue of the clinical phenotype.

scholarly journals Biogenesis of NDUFS3-less complex I indicates TMEM126A/OPA7 as an assembly factor of the ND4-module

2020 ◽  
Author(s):  
Luigi D’Angelo ◽  
Elisa Astro ◽  
Monica De Luise ◽  
Ivana Kurelac ◽  
Nikkitha Umesh-Ganesh ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Optic Atrophy ◽  
Complex I ◽  
Disease Gene ◽  
Mitochondrial Respiratory Chain ◽  
Cell Types ◽  
Catalytic Core ◽  
Assembly Factor ◽  
Functional Consequences ◽  
And Function

ABSTRACTComplex I (CI) is the largest enzyme of the mitochondrial respiratory chain and its defects are the main cause of mitochondrial disease. To understand the mechanisms regulating the extremely intricate biogenesis of this fundamental bioenergetic machine, we analyzed the structural and functional consequences of the ablation of NDUFS3, a non-catalytic core subunit. We prove that in diverse mammalian cell types a small amount of functional CI can still be detected in the complete absence of NDUFS3. In addition, we have determined the dynamics of CI disassembly when the amount of NDUFS3 is gradually decreased. The process of degradation of the complex occurs in a hierarchical and modular fashion where the ND4-module remains stable and bound to TMEM126A. We have thus, uncovered the function of TMEM126A, the product of a disease gene causing recessive optic atrophy, as a factor necessary for the correct assembly and function of CI.

scholarly journals Phylogeography of Aedes (Stegomyia) aegypti (L.) and Aedes (Stegomyia) albopictus (Skuse) (Diptera: Culicidae) based on mitochondrial DNA variations

2005 ◽  
Vol 86 (1) ◽  
pp. 1-11 ◽  
Author(s):  
LAURENCE MOUSSON ◽  
CATHERINE DAUGA ◽  
THOMAS GARRIGUES ◽  
FRANCIS SCHAFFNER ◽  
MARIE VAZEILLE ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Genetic Variation ◽  
East Asia ◽  
Ivory Coast ◽  
Nadh Dehydrogenase ◽  
South East Asia ◽  
Nadh Dehydrogenase Subunit ◽  
African Populations ◽  
The Tropics ◽  
Dna Variations

Aedes (Stegomyia) aegypti (L.) and Aedes (Stegomyia) albopictus (Skuse) are the most important vectors of the dengue and yellow-fever viruses. Both took advantage of trade developments to spread throughout the tropics from their native area: A. aegypti originated from Africa and A. albopictus from South-East Asia. We investigated the relationships between A. aegypti and A. albopictus mosquitoes based on three mitochondrial-DNA genes (cytochrome b, cytochrome oxidase I and NADH dehydrogenase subunit 5). Little genetic variation was observed for A. albopictus, probably owing to the recent spreading of the species via human activities. For A. aegypti, most populations from South America were found to be genetically similar to populations from South-East Asia (Thailand and Vietnam), except for one sample from Boa Vista (northern Amazonia), which was more closely related to samples from Africa (Guinea and Ivory Coast). This suggests that African populations of A. aegypti introduced during the slave trade have persisted in Boa Vista, resisting eradication campaigns.

scholarly journals Efficient selection and characterization of mutants of a human cell line which are defective in mitochondrial DNA-encoded subunits of respiratory NADH dehydrogenase.

1995 ◽  
Vol 15 (2) ◽  
pp. 964-974 ◽  
Author(s):  
G Hofhaus ◽  
G Attardi
Keyword(s):  
Mitochondrial Dna ◽  
Cell Line ◽  
Human Cell ◽  
Complex I ◽  
Mammalian Cells ◽  
Nadh Dehydrogenase ◽  
Frameshift Mutation ◽  
Human Cell Line ◽  
Mtdna Mutation ◽  
Selection Scheme

The mitochondrial NADH dehydrogenase (complex I) in mammalian cells is a multimeric enzyme consisting of approximately 40 subunits, 7 of which are encoded in mitochondrial DNA (mtDNA). Very little is known about the function of these mtDNA-encoded subunits. In this paper, we describe the efficient isolation from a human cell line of mutants affected in any of these subunits. In the course of analysis of eight mutants of the human cell line VA2B selected for their resistance to high concentrations of the complex I inhibitor rotenone, seven were found to be respiration deficient, and among these, six exhibited a specific defect of complex I. Transfer of mitochondria from these six mutants into human mtDNA-less cells revealed, surprisingly, in all cases a cotransfer of the complex I defect but not of the rotenone resistance. This result indicated that the rotenone resistance resulted from a nuclear mutation, while the respiration defect was produced by an mtDNA mutation. A detailed molecular analysis of the six complex I-deficient mutants revealed that two of them exhibited a frameshift mutation in the ND4 gene, in homoplasmic or in heteroplasmic form, resulting in the complete or partial loss, respectively, of the ND4 subunit; two other mutants exhibited a frameshift mutation in the ND5 gene, in near-homoplasmic or heteroplasmic form, resulting in the ND5 subunit being undetectable or strongly decreased, respectively. It was previously reported (G. Hofhaus and G. Attardi, EMBO J. 12:3043-3048, 1993) that the mutant completely lacking the ND4 subunit exhibited a total loss of NADH:Q1 oxidoreductase activity and a lack of assembly of the mtDNA-encoded subunits of complex I. By contrast, in the mutant characterized in this study in which the ND5 subunit was not detectable and which was nearly totally deficient in complex I activity, the capacity to assemble the mtDNA-encoded subunits of the enzyme was preserved, although with a decreased efficiency or a reduced stability of the assembled complex. The two remaining complex I-deficient mutants exhibited a normal rate of synthesis and assembly of the mtDNA-encoded subunits of the enzyme, and the mtDNA mutation(s) responsible for their NADH dehydrogenase defect remains to be identified. The selection scheme used in this work has proven to be very valuable for the isolation of mutants from the VA2B cell line which are affected in different mtDNA-encoded subunits of complex I and may be applicable to other cell lines.

scholarly journals Mitochondrial 10398A>G NADH-Dehydrogenase Subunit 3 of Complex I Is Frequently Altered in Intra-Axial Brain Tumors in Malaysia

2018 ◽  
Vol 6 (1) ◽  
pp. 31 ◽  
Author(s):  
Abdul Aziz Mohamed Yusoff ◽  
Fatin Najwa Zulfakhar ◽  
Siti Zulaikha Nashwa Mohd Khair ◽  
Wan Salihah Wan Abdullah ◽  
Jafri Malin Abdullah ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Complex I ◽  
Nadh Dehydrogenase ◽  
Nadh Dehydrogenase Subunit

scholarly journals Nonsynonymous variants in mt-Nd2, mt-Nd4, and mt-Nd5 are linked to effects on oxidative phosphorylation and insulin sensitivity in rat conplastic strains

2012 ◽  
Vol 44 (9) ◽  
pp. 487-494 ◽  
Author(s):  
Josef Houštěk ◽  
Kateřina Hejzlarová ◽  
Marek Vrbacký ◽  
Zdeněk Drahota ◽  
Vladimír Landa ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Complex I ◽  
Nuclear Genome ◽  
Chain Complex ◽  
Inbred Strains ◽  
Exercise Intolerance ◽  
Rrna Genes ◽  
Nonesterified Fatty Acid ◽  
Mitochondrial Genomes ◽  
Mtdna Sequence

Common inbred strains of the laboratory rat can be divided into four different mitochondrial DNA haplotype groups represented by the SHR, BN, LEW, and F344 strains. In the current study, we investigated the metabolic and hemodynamic effects of the SHR vs. LEW mitochondrial genomes by comparing the SHR to a new SHR conplastic strain, SHR-mtLEW; these strains are genetically identical except for their mitochondrial genomes. Complete mitochondrial DNA (mtDNA) sequence analysis comparing the SHR and LEW strains revealed gene variants encoding amino acid substitutions limited to a single mitochondrial enzyme complex, NADH dehydrogenase (complex I), affecting subunits 2, 4, and 5. Two of the variants in the mt-Nd4 subunit gene are located close to variants known to be associated with exercise intolerance and diabetes mellitus in humans. No variants were found in tRNA or rRNA genes. These variants in mt-Nd2, mt-Nd4, and mt-Nd5 in the SHR-mtLEW conplastic strain were linked to reductions in oxidative and nonoxidative glucose metabolism in skeletal muscle. In addition, SHR-mtLEW conplastic rats showed increased serum nonesterified fatty acid levels and resistance to insulin stimulated incorporation of glucose into adipose tissue lipids. These results provide evidence that inherited variation in mitochondrial genes encoding respiratory chain complex I subunits, in the absence of variation in the nuclear genome and other confounding factors, can influence glucose and lipid metabolism when expressed on the nuclear genetic background of the SHR strain.

scholarly journals Phylogenetic Relationships of the Madagascar Pygmy Kingfisher (Ispidina Madagascariensis)

The Auk ◽  
2005 ◽  
Vol 122 (4) ◽  
pp. 1271-1280
Author(s):  
Ben D. Marks ◽  
David E. Willard
Keyword(s):  
Mitochondrial Dna ◽  
Phylogenetic Relationships ◽  
Nadh Dehydrogenase ◽  
Southeast Asian ◽  
African Origin ◽  
Nadh Dehydrogenase Subunit ◽  
Base Pairs ◽  
Phylogenetic Hypotheses ◽  
Tree Building ◽  
African Genus

Abstract The avifauna of Madagascar presents a complicated taxonomic and biogeographic problem. Although Madagascar was once connected to Africa, the birds of the island are not all of African origin. The Madagascar Pygmy Kingfisher (Ispidina madagascariensis) is sometimes placed in the African genus Ispidina and sometimes in the Southeast Asian genus Ceyx. We sequenced 755 base pairs of mitochondrial DNA from a fragment of the NADH dehydrogenase subunit II (ND2) and from the complete NADH dehydrogenase subunit III (ND3). We used these data to construct phylogenetic hypotheses for the Alcedinidae. Using these phylogenies, we evaluate previous hypotheses of relationships of I. madagascariensis. Although we cannot reject the hypothesis that I. madagascariensis is indeed a member of Ispidina, tree-building analyses support a relationship not with Ispidina or Ceyx, but instead with members of the African genus Corythornis. These data suggest that certain behaviors and plumage types have evolved several times in the Alcedinidae. Relations Phylogénétiques de Ispidina madagascariensis

scholarly journals First molecular description, phylogeny and genetic variation of Taenia hydatigena from Nigerian sheep and goats based on three mitochondrial genes

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
John A. Ohiolei ◽  
Joshua Luka ◽  
Guo-Qiang Zhu ◽  
Hong-Bin Yan ◽  
Li Li ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Genetic Variation ◽  
Dna Markers ◽  
Nadh Dehydrogenase ◽  
Mitochondrial Genes ◽  
Full Length ◽  
Nadh Dehydrogenase Subunit ◽  
Taenia Hydatigena ◽  
Sheep And Goats ◽  
Geographical Regions

Abstract Background Cysticercosis caused by the metacestode larval stage of Taenia hydatigena is a disease of veterinary and economic importance. A considerable level of genetic variation among isolates of different intermediate hosts and locations has been documented. Generally, data on the genetic population structure of T. hydatigena is scanty and lacking in Nigeria. Meanwhile, similar findings in other cestodes like Echinococcus spp. have been found to be of epidemiological importance. Our aim, therefore, was to characterize and compare the genetic diversity of T. hydatigena population in Nigeria based on three mitochondrial DNA markers as well as to assess the phylogenetic relationship with populations from other geographical regions. Methods In the present study, we described the genetic variation and diversity of T. hydatigena isolates from Nigerian sheep and goats using three full-length mitochondrial genes: the cytochrome c oxidase subunit 1 (cox1), NADH dehydrogenase subunit 1 (nad1), and NADH dehydrogenase subunit 5 (nad5). Results The median-joining network of concatenated cox1-nad1-nad5 sequences indicated that T. hydatigena metacestodes of sheep origin were genetically distinct from those obtained in goats and this was supported by high FST values of nad1, cox1, and concatenated cox1-nad1-nad5 sequences. Genetic variation was also found to be higher in isolates from goats than from sheep. Conclusions To the best of our knowledge, the present study described the genetic variation of T. hydatigena population for the first time in Nigeria using full-length mitochondrial genes and suggests the existence of host-specific variants. The population indices of the different DNA markers suggest that analysis of long mitochondrial DNA fragments may provide more information on the molecular ecology of T. hydatigena. We recommend that future studies employ long mitochondrial DNA sequence in order to provide reliable data that would explain the extent of genetic variation in different hosts/locations and the biological and epidemiological significance.

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