Disorders of mitochondrial protein synthesis

Jacobs, Howard T.

doi:10.1093/hmg/ddg285

Cited by 85 publications

(70 citation statements)

References 69 publications

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“…Many studies have implicated pathogenic point mutations in tRNAs Leu(UUR) in the dysfunctions associated with MELAS mutations (15,33). These dysfunctions include impaired termination (34), impaired pre-tRNA processing (35), decreased stability and aminoacylation (36), and abnormal conformation (37), and commonly lead to a decreased steady-state level of the normal aminoacylated tRNA, which in turn leads to reduced protein synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…In the case of MELAS, a decline in enzymatic activity and a decrease in protein synthesis were observed in cybrid cells containing a high ratio of mutated mtDNA (12)(13)(14). Several lines of studies proposed dysfunction of the mutant tRNAs Leu(UUR) as a possible outcome arising directly from the MELAS mutations, which would in turn cause a decrease in respiratory activity (15). However, there is as yet no conclusive evidence for a molecular mechanism of mitochondrial dysfunction induced by pathogenic point mutations.…”

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confidence: 99%

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Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease

Kirino

Yasukawa

Ohta

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

261

224

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Point mutations in the mitochondrial (mt) tRNA Leu(UUR) gene are responsible for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), a subgroup of mitochondrial encephalomyopathic diseases. We previously showed that mt tRNA Leu(UUR) with an A3243G or T3271C mutation derived from patients with MELAS are deficient in a normal taurinecontaining modification ( m 5 U; 5-taurinomethyluridine) at the anticodon wobble position. To examine decoding disorder of the mutant tRNA due to the wobble modification deficiency independent of the pathogenic point mutation itself, we used a molecular surgery technique to construct an mt tRNA Leu(UUR) molecule lacking the taurine modification but without the pathogenic mutation. This ''operated'' mt tRNA Leu(UUR) without the taurine modification showed severely reduced UUG translation but no decrease in UUA translation. We thus concluded that the UUG codon-specific translational defect of the mutant mt tRNAs Leu(UUR) is the primary cause of MELAS at the molecular level. This result could explain the complex I deficiency observed clinically in MELAS.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease

Kirino

Yasukawa

Ohta

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

261

224

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“…Single mtDNA deletions cause KSS, CPEO, or PS, whose affected tissues show impaired electron transport activity, ATP production, and mitochondrial protein synthesis [26,56,57]. Muscle biopsies from patients with KSS or CPEO show ragged-red fibers and cytochrome oxidase-negative fibers [58,59].…”

Section: Discussionmentioning

confidence: 99%

“…Deletions of the mitochondrial genome erase not only subunits of the respiratory chain that must co-operate with nuclear-encoded subunits [63], but also tRNAs necessary for mitochondrial protein synthesis [57].…”

Section: Deletions Inhibit the Ubiquitin And Proteasome Systemmentioning

confidence: 99%

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Alemi

Prigione

Wong

et al. 2007

Free Radical Biology and Medicine

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Deletions within the mitochondrial DNA (mtDNA) cause Kearns Sayre Syndrome (KSS) and Chronic Progressive External Opthalmoplegia (CPEO). The clinical signs of KSS include muscle weakness, heart block, pigmentary retinopathy, ataxia, deafness, short stature, and dementia. The identical deletions occur and rise exponentially as humans age, particularly in substantia nigra. Deletions at >30% concentration cause deficits in basic bioenergetic parameters, including membrane potential and ATP synthesis, but it is poorly understood how these alterations cause the pathologies observed in patients. To better understand the consequences of mtDNA deletions, we microarrayed 6 cell types containing mtDNA deletions from KSS and CPEO patients. There was a prominent inhibition of transcripts encoding ubiquitin-mediated proteasome activity, and a prominent induction of transcripts involved in the AMP kinase pathway, macroautophagy, and amino acid degradation. In mutant cells, we confirmed a decrease in proteasome biochemical activity, significantly lower concentration of several amino acids, and induction of an autophagic transcript. An interpretation consistent with the data is that mtDNA deletions increase protein damage, inhibit the ubiquitin-proteasome system, decrease amino acid salvage, and activate autophagy. This provides a novel pathophysiological mechanism for these diseases, and suggests potential therapeutic strategies.

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“…Mitochondrial dysfunctions such as MELAS or MERRF could have multiple causes, including impaired termination of transcription, decreased RNase P processing, decreased tRNA stability, aminoacylation, or abnormal conformations, 11,12 which would lead to decreased steady-state levels of the normal aminoacylated tRNAs and result in reduced mitochondrial protein synthesis. However, particularly in the case of MELAS, the reduced mitochondrial protein synthesis in cells with these pathogenic mutations cannot explain why these cells also show decreased respiratory activity or oxygen consumption since the mitochondrial protein synthesis level does not seem to parallel the enzymatic activity involved in these processes.…”

Section: Role Of the Rna Modification Disorder In The Molecular Pathomentioning

confidence: 99%

Human Mitochondrial Diseases Associated with tRNA Wobble Modification Deficiency

Kirino

Suzuki

2005

RNA Biology

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A growing number of mutations in mitochondrial (mt) tRNA genes have been found to associate with human mitochondrial diseases. Our previous analysis of mutant mt tRNAs isolated from cells derived from patients with mitochondrial diseases revealed the lack of a post-transcriptional taurine-modification at the anticodon wobble uridine in two mt tRNAs bearing typical pathogenic mutations: mt tRNA Leu(UUR) with either the MELAS 3243 or 3271 mutation and mt tRNA Lys with the MERRF 8344 mutation. We here summarize our recent studies that clarify the molecular basis of the defective mitochondrial translation caused by this wobble modification deficiency. The MERRF mt tRNA Lys lacking the wobble modification cannot translate either of its codons (AAA and AAG), while the translational activity of MELAS mt tRNA Leu(UUR) lacking wobble modification is more depressed in decoding of UUG codon than UUA codon. These findings suggest that the wobble modification deficiency plays a primary role in the molecular pathogenesis of the MELAS and MERRF mitochondrial diseases.Point mutations as well as large scale deletions in mitochondrial DNA (mtDNA) are associated with a wide spectrum of human diseases arising from mitochondrial dysfunction. 1,2 Over 150 different pathogenic mutations have been reported so far, more than half of which are located within mt tRNA genes. 1,2 The clinical features of mitochondrial diseases often depend on the mt tRNA species and/or the positions of the mutations involved. However, it is not clear how, at the molecular level, the mutant mt tRNAs actually cause mitochondrial dysfunction and specify the clinical features they generate. If a pathogenic mutation in the mt tRNA gene does not affect mtDNA replication or transcription of the corresponding mt tRNA, it can be assumed that its deleterious effect is exerted at the post-transcriptional level. In other words, it may affect mt tRNA maturation, modification, folding, or aminoacylation, its association with translation factors, and/or various functions on the ribosome. To elucidate the essential molecular pathogenesis of mitochondrial diseases, detailed structural and functional analyses of the mutant mt tRNAs are thus required.We have recently found that of the various post-transcriptional events that an mt tRNA mutation could potentially impair, some mutant mt tRNAs fail to undergo particular post-transcriptional modifications. We previously identified two novel taurine-containing modified uridines [5-taurinemethyluridine (τm 5 U) and 5-taurinomethyl2-thiouridine (τm 5 s 2 U)] at the anticodon first (wobble) position of some species of mammalian mt tRNAs (Fig. 1). 3 What is more, these taurine-containing modifications were lacking in the mutant mt tRNAs from two typical mitochondrial diseases. Our additional analyses suggest that the absence of these modifications can be the main cause of the mitochondrial dysfunction associated with these diseases.

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Disorders of mitochondrial protein synthesis

Cited by 85 publications

References 69 publications

Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease

Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Human Mitochondrial Diseases Associated with tRNA Wobble Modification Deficiency

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