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

Kirino, Yohei; Yasukawa, Takehiro; Ohta, Shigeo; Akira, Shigeo; Ishihara, K.; Watanabe, Kimitsuna; Suzuki, Tsutomu

doi:10.1073/pnas.0405173101

Cited by 252 publications

(225 citation statements)

References 53 publications

Supporting

Mentioning

213

Contrasting

Unclassified

Order By: Relevance

“…Hmt-tRNA pathogenic mutations can also have indirect influences on the anticodon. For example, several mutations outside the anticodon loop of hmttRNA Lys and hmt-tRNA Leu result in modification defects at U34 (18)(19)(20). The unmodified U loses the ability to wobble with G, which in turn leads to decoding deficiencies.…”

Section: Discussionmentioning

confidence: 99%

“…Diseases associated with hmt-tRNA point mutations include MERRF (myoclonic epilepsy with ragged red fibers), MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), and deafness (2)(3)(4). Pathogenic mutations of hmt-tRNAs have been shown to affect global tRNA structure (5)(6)(7)(8), tRNA processing (9-13), modification (14)(15)(16)(17)(18)(19)(20), aminoacylation (7,(21)(22)(23)(24)(25)(26), and translation efficiency (27)(28)(29). However, little is known about the precise pathogenic mechanisms of the vast majority of hmt-tRNA mutations, hindering the development of appropriate treatments.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Pathogenic mechanism of a human mitochondrial tRNA ^Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

Ling

Roy

Qin

et al. 2007

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

View full text Add to dashboard Cite

Human mitochondrial tRNA (hmt-tRNA) mutations are associated with a variety of diseases including mitochondrial myopathies, diabetes, encephalopathies, and deafness. Because the current understanding of the precise molecular mechanisms of these mutations is limited, there is no efficient method to treat their associated mitochondrial diseases. Here, we use a variety of known mutations in hmt-tRNA Phe to investigate the mechanisms that lead to malfunctions. We tested the impact of hmt-tRNA Phe mutations on aminoacylation, structure, and translation elongation-factor binding. The majority of the mutants were pleiotropic, exhibiting defects in aminoacylation, global structure, and elongation-factor binding. One notable exception was the G34A anticodon mutation of hmt-tRNA Phe (mitochondrial DNA mutation G611A), which is associated with MERRF (myoclonic epilepsy with ragged red fibers). In vitro, the G34A mutation decreases aminoacylation activity by 100-fold, but does not affect global folding or recognition by elongation factor. Furthermore, G34A hmt-tRNA Phe does not undergo adenosine-to-inosine (A-to-I) editing, ruling out miscoding as a possible mechanism for mitochondrial malfunction. To improve the aminoacylation state of the mutant tRNA, we modified the tRNA binding domain of the nucleus-encoded human mitochondrial phenylalanyl-tRNA synthetase, which aminoacylates hmt-tRNA Phe with cognate phenylalanine. This variant enzyme displayed significantly improved aminoacylation efficiency for the G34A mutant, suggesting a general strategy to treat certain classes of mitochondrial diseases by modification of the corresponding nuclear gene.aminoacyl-tRNA synthetase ͉ translation ͉ mitochondria

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Pathogenic mechanism of a human mitochondrial tRNA ^Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

Ling

Roy

Qin

et al. 2007

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

View full text Add to dashboard Cite

show abstract

“…Although the MELAS and MERRF pathogenic point mutations both impair the wobble modification of the mutant tRNAs, each mutant tRNA shows a distinct pattern of abnormal codon recognition. 21,29 This indicates that pathogenic mutations of this nature result in a severe phenotype that is incompatible with embryogenesis and development. In contrast, pathogenic mutations that result in only a mild phenotype or cause an RNA modification deficiency may not hamper development and only manifest themselves later as mitochondrial diseases.…”

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

confidence: 99%

“…In addition, we also estimated the negative effect in decoding the cognate UUA codon that the pathogenic point mutation has by itself, independent of the wobble modification deficiency. 21 The MELAS mt tRNA Leu(UUR) with the A3243G mutation showed a more severe reduction in UUA decoding than the mt tRNA Leu(UUR) with the T3271C mutation. This observation is consistent with the different translational activities of the MELAS cybrid cells that bear either of these two point mutations.…”

Section: Distinct Patterns Of Abnormal Codon Recognition Caused By Thmentioning

confidence: 99%

“…21 To do this, we employed a molecular surgery technique to construct an artificial mt tRNA Leu(UUR) molecule that has a completely normal sequence and bears all the modified bases except for the taurinemodification at the wobble position. This surgically altered mt tRNA Leu(UUR) showed severely reduced UUG translation but no decrease in UUA translation.…”

Section: Distinct Patterns Of Abnormal Codon Recognition Caused By Thmentioning

confidence: 99%

See 1 more Smart Citation

Human Mitochondrial Diseases Associated with tRNA Wobble Modification Deficiency

Kirino

Suzuki

2005

RNA Biology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

The epitranscriptome in translation regulation: mRNA and tRNA modifications as the two sides of the same coin?

Ranjan

Leidel

2019

FEBS Letters

View full text Add to dashboard Cite

Translation of mRNA is a highly regulated process that is tightly coordinated with cotranslational protein maturation. Recently, mRNA modifications and tRNA modifications – the so called epitranscriptome – have added a new layer of regulation that is still poorly understood. Both types of modifications can affect codon–anticodon interactions, thereby affecting mRNA translation and protein synthesis in similar ways. Here, we describe an updated view on how the different types of modifications can be mapped, how they affect translation, how they trigger phenotypes and discuss how the combined action of mRNA and tRNA modifications coordinate translation in health and disease.

show abstract

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

Cited by 252 publications

References 53 publications

Pathogenic mechanism of a human mitochondrial tRNA ^Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

Pathogenic mechanism of a human mitochondrial tRNA ^Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

Human Mitochondrial Diseases Associated with tRNA Wobble Modification Deficiency

The epitranscriptome in translation regulation: mRNA and tRNA modifications as the two sides of the same coin?

Contact Info

Product

Resources

About

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

Cited by 252 publications

References 53 publications

Pathogenic mechanism of a human mitochondrial tRNA Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

Pathogenic mechanism of a human mitochondrial tRNA Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

Human Mitochondrial Diseases Associated with tRNA Wobble Modification Deficiency

The epitranscriptome in translation regulation: mRNA and tRNA modifications as the two sides of the same coin?

Contact Info

Product

Resources

About

Pathogenic mechanism of a human mitochondrial tRNA ^Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

Pathogenic mechanism of a human mitochondrial tRNA ^Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome