Mutant Mitochondrial Elongation Factor G1 and Combined Oxidative Phosphorylation Deficiency

Coenen, Marieke J. H.; Antonická, Hana; Ugalde, Cristina; Sasarman, Florin; Rossi, R.; Heister, J. G. A. M.; Newbold, Robert F.; Trijbels, Frans J.M.; Heuvel, Lambert P. van den; Shoubridge, Eric A.; Smeitink, Jan A.M.

doi:10.1056/nejmoa041878

Cited by 172 publications

(140 citation statements)

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“…24 They found COI and COIII translation to be most severely disturbed, but in contrast to our results ATP6 showed a profoundly decreased synthesis as well. Increased synthesis of ATP6 and ATP8, as we observed for our tRNA Trp and tRNA Arg mutations, has been reported before [29][30][31][32] and has been suggested to be caused by the fact that bicistronic mRNAs can be translated more efficiently than monocistronic mRNAs, thereby giving the translation of ATP6 and ATP8 an advantage. 32 Many patients with a tRNA Trp mutation, including our patient, show developmental delay, gastrointestinal symptoms and failure to thrive.…”

Section: Discussionsupporting

confidence: 81%

Functional consequences of mitochondrial tRNATrp and tRNAArg mutations causing combined OXPHOS defects

et al. 2009

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Combined oxidative phosphorylation (OXPHOS) system deficiencies are a group of mitochondrial disorders that are associated with a range of clinical phenotypes and genetic defects. They occur in approximately 30% of all OXPHOS disorders and around 4% are combined complex I, III and IV deficiencies. In this study we present two mutations in the mitochondrial tRNA Trp (MT-TW) and tRNA Arg (MT-TR) genes, m.5556G4A and m.10450A4G, respectively, which were detected in two unrelated patients showing combined OXPHOS complex I, III and IV deficiencies and progressive multisystemic diseases. Both mitochondrial tRNA mutations were almost homoplasmic in fibroblasts and muscle tissue of the two patients and not present in controls. Patient fibroblasts showed a general mitochondrial translation defect. The mutations resulted in lowered steady-state levels and altered conformations of the tRNAs. Cybrid cell lines showed similar tRNA defects and impairment of OXPHOS complex assembly as patient fibroblasts. Our results show that these tRNA Trp and tRNA Arg mutations cause the combined OXPHOS deficiencies in the patients, adding to the still expanding group of pathogenic mitochondrial tRNA mutations.

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Section: Discussionsupporting

confidence: 81%

Functional consequences of mitochondrial tRNATrp and tRNAArg mutations causing combined OXPHOS defects

et al. 2009

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“…12,20 The clinical symptomatology in our patient is reminiscent of the somewhat milder phenotype described by Valente et al, 21 which was characterized by feeding problems, axial hypotonia, increased limb muscle tone and infantile-onset epilepsy. Notably, liver dysfunction was absent, as in our patient.…”

Section: Discussionsupporting

confidence: 60%

“…Whereas b-hydroxybutyrate levels in blood and urine were normal in our patient, Valente et al reported increased levels. The biochemical findings appear to correlate with disease severity: our patient showed lower blood lactate levels (4.9 versus 17 mmol/l) and lactate:pyruvate ratios (22 versus 38) compared with the first reported EFG1 patient, 20 suggesting a more modest disturbance of mitochondrial functioning.…”

Section: Discussionsupporting

confidence: 49%

“…The first patient harbored a homozygous mutation in the GTP-binding domain I (Asn174Ser), 20 and subsequent reports revealed compound heterozygous missense and nonsense mutations affecting other domains of EFG1: Ser321Pro (on the boundary between domains I and II)+Leu607X (predicted to remove domain V) 12 and Met496Arg (in domain III)+Arg47X (predicted to eliminate basically all domains). 21 Mitochondrial translation was impaired in a similar manner in all patients: a severe overall decrease in the rate of mitochondrial translation, with the expression of subunits ND5, ND6, COX I, II and III generally being the lowest.…”

Section: Discussionmentioning

confidence: 99%

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Mutation in subdomain G' of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle

et al. 2010

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The mitochondrial translation system is responsible for the synthesis of 13 proteins required for oxidative phosphorylation (OXPHOS), the major energy-generating process of our cells. Mitochondrial translation is controlled by various nuclear encoded proteins. In 27 patients with combined OXPHOS deficiencies, in whom complex II (the only complex that is entirely encoded by the nuclear DNA) showed normal activities, and mutations in the mitochondrial genome as well as polymerase gamma were excluded, we screened all mitochondrial translation factors for mutations. Here, we report a mutation in mitochondrial elongation factor G1 (GFM1) in a patient affected by severe, rapidly progressive mitochondrial encephalopathy. This mutation is predicted to result in an Arg250Trp substitution in subdomain G' of the elongation factor G1 protein and is presumed to hamper ribosome-dependent GTP hydrolysis. Strikingly, the decrease in enzyme activities of complex I, III and IV detected in patient fibroblasts was not found in muscle tissue. The OXPHOS system defects and the impairment in mitochondrial translation in fibroblasts were rescued by overexpressing wild-type GFM1, establishing the GFM1 defect as the cause of the fatal mitochondrial disease. Furthermore, this study evinces the importance of a thorough diagnostic biochemical analysis of both muscle tissue and fibroblasts in patients suspected to suffer from a mitochondrial disorder, as enzyme deficiencies can be selectively expressed.

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“…Changes in the normal pattern of mitochondrial protein synthesis, as revealed through radioactive labeling, have served to identify and confi rm causal mutations, and to analyze the pathogenic mechanism of mitochondrial diseases caused by mutations in components of the mitochondrial translation system that are encoded by either the mitochondrial ( 5-10 ) or the nuclear genome (11)(12)(13)(14)(15)(16)(17)(18)(19)(20) …”

Section: Introductionmentioning

confidence: 99%

Radioactive Labeling of Mitochondrial Translation Products in Cultured Cells

Sasarman

Shoubridge

2011

Methods in Molecular Biology

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The mammalian mitochondrial genome contains 37 genes, 13 of which encode polypeptide subunits in the enzyme complexes of the oxidative phosphorylation system. The other genes encode the rRNAs and tRNAs necessary for their translation. The mitochondrial translation machinery is located in the mitochondrial matrix, and is exclusively dedicated to the synthesis of these 13 enzyme subunits. Mitochondrial disease in humans is often associated with defects in mitochondrial translation. This can manifest as a global decrease in the rate of mitochondrial protein synthesis, a decrease in the synthesis of specifi c polypeptides, the synthesis of abnormal polypeptides, or in altered stability of specifi c translation products. All of these changes in the normal pattern of mitochondrial translation can be assessed by a straightforward technique that takes advantage of the insensitivity of the mitochondrial translation machinery to antibiotics that completely inhibit cytoplasmic translation. Thus, specifi c radioactive labeling of the mitochondrial translation products can be achieved in cultured cells, and the results can be visualized on gradient gels. The analysis of mitochondrial translation in cells cultured from patient biopsies is useful in the study of disease-causing mutations in both the mitochondrial and the nuclear genomes.Key words: Mitochondria , Oxidative Phosphorylation (OXPHOS) , Mitochondrial DNA (mtDNA) , Pulse-chase labeling , Mitochondrial translation Pulse labeling of the mitochondrial translation products is useful for the assessment of both the individual and global rates of synthesis of the 13 proteins encoded by the mtDNA, and pulsechase labeling permits the evaluation of the stability of the newly synthesized polypeptides. In both cases, cells are exposed to a mixture of radiolabeled methionine and cysteine in the presence of an inhibitor of cytoplasmic protein synthesis, which results in the specifi c radiolabeling of the mitochondrial translation products.

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Mutant Mitochondrial Elongation Factor G1 and Combined Oxidative Phosphorylation Deficiency

Cited by 172 publications

References 24 publications

Functional consequences of mitochondrial tRNATrp and tRNAArg mutations causing combined OXPHOS defects

Functional consequences of mitochondrial tRNATrp and tRNAArg mutations causing combined OXPHOS defects

Mutation in subdomain G' of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle

Radioactive Labeling of Mitochondrial Translation Products in Cultured Cells

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