A New Mitochondrial Transfer RNAPro Gene Mutation Associated With Myoclonic Epilepsy With Ragged-Red Fibers and Other Neurological Features

Blakely, Emma L.; Trip, S Anand; Swalwell, Helen; He, Langping; Wren, Damian; Rich, Philip; Turnbull, Douglass M.; Omer, Salah; Taylor, Robert W.

doi:10.1001/archneurol.2008.576

Cited by 44 publications

(17 citation statements)

References 19 publications

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“…Interestingly, mutations in several human mt-tRNAs have been reported to cause isolated complex I deficiency, with no obvious effect on other respiratory complexes. These include the mttRNA for Pro, Trp, Lys, Leu (UUR), and Ser (AGY) (Shoffner et al, 1990;Arenas et al, 1999;Blakely et al, 2009;Da Pozzo et al, 2009;Calvo et al, 2010;Swalwell et al, 2011). Although little is known about mitochondrial translation in plants, a recent study (Kwasniak et al, 2013) described how silencing of RPS10, a nuclear-encoded subunit of the small ribosomal subunit in mitochondria, resulted in an altered pattern of in organellotranslated peptides.…”

Section: Discussionmentioning

confidence: 99%

The Evolutionarily Conserved Iron-Sulfur Protein INDH Is Required for Complex I Assembly and Mitochondrial Translation in Arabidopsis

et al. 2013

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The assembly of respiratory complexes is a multistep process, requiring coordinate expression of mitochondrial and nuclear genes and cofactor biosynthesis. We functionally characterized the iron-sulfur protein required for NADH dehydrogenase (INDH) in the model plant Arabidopsis thaliana. An indh knockout mutant lacked complex I but had low levels of a 650-kD assembly intermediate, similar to mutations in the homologous NUBPL (nucleotide binding protein-like) in Homo sapiens. However, heterozygous indh/+ mutants displayed unusual phenotypes during gametogenesis and resembled mutants in mitochondrial translation more than mutants in complex I. Gradually increased expression of INDH in indh knockout plants revealed a significant delay in reassembly of complex I, suggesting an indirect role for INDH in the assembly process. Depletion of INDH protein was associated with decreased 35 S-Met labeling of translation products in isolated mitochondria, whereas the steady state levels of several mitochondrial transcripts were increased. Mitochondrially encoded proteins were differentially affected, with near normal levels of cytochrome c oxidase subunit2 and Nad7 but little Nad6 protein in the indh mutant. These data suggest that INDH has a primary role in mitochondrial translation that underlies its role in complex I assembly.

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Section: Discussionmentioning

confidence: 99%

The Evolutionarily Conserved Iron-Sulfur Protein INDH Is Required for Complex I Assembly and Mitochondrial Translation in Arabidopsis

et al. 2013

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“…Lactate and pyruvate are commonly elevated in serum at rest and increase excessively after moderate physical activities [5]. The m.8344A>G mutation in the mtDNA gene MT-TK, which encodes mitochondrial transfer (t)RNA Lysine is the most common mutation asso< ciated with MERRF syndrome, although other mutations in tRNA Lysine or genes encoding different tRNAs have been identified in MERRF patients [6,7]. The m.8344A>G mutation, which is localized in the T-arm of the tRNA, is one of the most studied and prevalent pathological mtDNA mutations [8].…”

Section: Introductionmentioning

confidence: 99%

Recovery of MERRF Fibroblasts and Cybrids Pathophysiology by Coenzyme Q10

et al. 2012

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Mitochondrial DNA mutations are an important cause of human disease for which there is no effective treatment. Myoclonic epilepsy with ragged-red fibers (MERRF) is a mitochondrial disease usually caused by point mutations in transfer RNA genes encoded by mitochondrial DNA. The most common mutation associated with MERRF syndrome, m.8344A>G in the gene MT-TK, which encodes transfer RNA Lysine , affects the translation of all mitochondrial DNA encoded proteins. This impairs the assembly of the electron transport chain complexes leading to decreased mitochondrial respiratory function. Here we report on how this mutation affects mitochondrial function in primary fibroblast cultures established from patients harboring the A8344G mutation. Coenzyme Q 10 (CoQ) levels, as well as mitochondrial respiratory chain activity, and mitochondrial protein expression levels were significantly decreased in MERRF fibroblasts. Mitotracker staining and imaging analysis of individual mitochondria indicated the presence of small, rounded, depolarized mitochondria in MERRF fibroblasts. Mitochondrial dysfunction was associated with increased oxidative stress and increased degradation of impaired mitochondria by mitophagy. Transmitochondrial cybrids harboring the A8344G mutation also showed CoQ deficiency, mitochondrial dysfunction, and increased mitophagy activity. All these abnormalities in patient-derived fibroblasts and cybrids were partially restored by CoQ supplementation, indicating that these cell culture models may be suitable for screening and validation of novel drug candidates for MERRF disease.

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“…Besides, lactate and pyruvate are commonly elevated in serum at rest and increased excessively after moderate physical activities [12]. The A8344G mutation in the tRNA Lys gene of mtDNA is the most common mutation associated with MERRF syndrome, although few less frequent point mutations of mtDNA were also found in MERRF patients [13,14]. Besides, molecular genetic studies of several MERRF pedigrees and biochemical studies of skin fibroblasts showed a positive correlation between the A8344G mutation in the tRNA Lys gene of mtDNA and the reduction in the activities of respiratory enzyme Complexes I and IV [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA Mutation-Elicited Oxidative Stress, Oxidative Damage, and Altered Gene Expression in Cultured Cells of Patients with MERRF Syndrome

Wu¹,

Ma²,

Wu³

et al. 2010

Mol Neurobiol

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Myoclonic epilepsy and ragged-red fibers (MERRF) syndrome is a rare disorder characterized by myoclonus, muscle weakness, cerebellar ataxia, heart conduction block, and dementia. It has been documented that 80-90% of the patients with MERRF syndrome are caused by the A8344G mutation in the tRNA(Lys) gene of mitochondrial DNA (mtDNA). We and other investigators have reported that the mtDNA mutation results in not only inefficient generation of adenosine triphosphate but also increased production of reactive oxygen species (ROS) in cultured cells harboring A8344G mutation of mtDNA. In addition, we found an imbalance in the gene expression of antioxidant enzymes in the skin fibroblasts of MERRF patients. The mRNA, protein, and enzyme activity levels of manganese-superoxide dismutase were increased, but those of Cu,Zn-SOD, catalase, and glutathione peroxidase did not show significant changes. Recently, we showed that the excess ROS could damage voltage-dependent anion channel, prohibitin, Lon protease, and aconitase in the MERRF cells. Moreover, there was a dramatic increase in the gene expression and activity of matrix metalloproteinase 1, which may contribute to the cytoskeleton remodeling involved in the weakness and atrophy of muscle commonly seen in MERRF patients. Taken together, we suggest that mtDNA mutation-elicited oxidative stress, oxidative damage, and altered gene expression are involved in the pathogenesis and progression of MERRF syndrome.

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A New Mitochondrial Transfer RNAPro Gene Mutation Associated With Myoclonic Epilepsy With Ragged-Red Fibers and Other Neurological Features

Cited by 44 publications

References 19 publications

The Evolutionarily Conserved Iron-Sulfur Protein INDH Is Required for Complex I Assembly and Mitochondrial Translation in Arabidopsis

The Evolutionarily Conserved Iron-Sulfur Protein INDH Is Required for Complex I Assembly and Mitochondrial Translation in Arabidopsis

Recovery of MERRF Fibroblasts and Cybrids Pathophysiology by Coenzyme Q10

Mitochondrial DNA Mutation-Elicited Oxidative Stress, Oxidative Damage, and Altered Gene Expression in Cultured Cells of Patients with MERRF Syndrome

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