Increased mitochondrial processing intermediates associated with three tRNALeu(UUR) gene mutations

Koga, Akimasa; Koga, Yasutoshi; Akita, Yukihiro; Fukiyama, Ryo; Ueki, Isao; Yatsuga, Shuichi; Matsuishi, Toyojiro

doi:10.1016/s0960-8966(02)00267-5

Cited by 24 publications

(19 citation statements)

References 9 publications

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“…Proximity to the 3′ cleavage site is not, however, a requirement for impairing the endonucleolytic step, since it was shown that the mutations 3243A>G, 3271T>C and 3302T>C all lead to the accumulation of RNA19 in vivo in biopsy samples of patients presenting with the mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS) syndrome (28). These authors showed that RNA19 molecules containing these mutations are more abundant in RNA samples than was predicted from the levels of DNA heteroplasmy suggesting that processing may be affected by mutations throughout the tRNA.…”

Section: Discussionmentioning

confidence: 99%

Molecular dysfunction associated with the human mitochondrial 3302A>G mutation in the MTTL1 (mt-tRNALeu(UUR)) gene

Maniura‐Weber¹,

Helm

Engemann³

et al. 2006

Nucleic Acids Research

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The gene encoding mt-tRNALeu(UUR), MT-TL1, is a hotspot for pathogenic mtDNA mutations. Amongst the first to be described was the 3302A>G transition which resulted in a substantial accumulation in patient muscle of RNA19, an unprocessed RNA intermediate including mt-16S rRNA, mt-tRNALeu(UUR) and MTND1. We have now been able to further assess the molecular aetiology associated with 3302A>G in transmitochondrial cybrids. Increased steady-state levels of RNA19 was confirmed, although not to the levels previously reported in muscle. This data was consistent with an increase in RNA19 stability. The mutation resulted in decreased mt-tRNALeu(UUR) levels, but its stability was unchanged, consistent with a defect in RNA19 processing responsible for low tRNA levels. A partial defect in aminoacylation was also identified, potentially caused by an alteration in tRNA structure. These deficiencies lead to a severe defect in respiration in the transmitochondrial cybrids, consistent with the profound mitochondrial disorder originally associated with this mutation.

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Section: Discussionmentioning

confidence: 99%

Molecular dysfunction associated with the human mitochondrial 3302A>G mutation in the MTTL1 (mt-tRNALeu(UUR)) gene

Maniura‐Weber¹,

Helm

Engemann³

et al. 2006

Nucleic Acids Research

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“…13 The A3243G mutation shows dominant negative effects in the processing system of mitochondrial transcription seen in both trans-mitochondrial cell 13 and muscle in MELAS patients. 14,15 Molecular mechanisms described earlier may contribute to respiratory chain enzyme defects, especially complexes I and IV, and lead to the mitochondrial cytopathy seen in the MELAS patients. 4,16 Moreover, the A3243G mutation affects the nuclear background, resulting in a high glycolytic rate, increased lactate produc-tion, reduced glucose oxidation, impaired NADHresponse, reduced mitochondrial membrane potential, markedly reduced ATP production, deranged cell calcium handling with an increased cytosolic calcium handling with an increased cytosolic calcium load, an increased amount of reactive oxygen species in cybrid cells, reduced insulin secretion, premature aging, and deregulation of genes involved in the metabolism of amino groups and urea genesis.…”

Section: Mitochondrial Cytopathy (Molecular and Cellular Defects) In mentioning

confidence: 99%

MELAS and l‐arginine therapy: pathophysiology of stroke‐like episodes

Koga

Povalko

Nishioka

et al. 2010

Annals of the New York Academy of Sciences

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100

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Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited multisystem mitochondrial disorder. Although many molecular and cellular mechanisms have been discovered leading to mitochondrial cytopathy, the pathogenic mechanism of stroke-like episodes seen in MELAS has not been clarified yet. According to the muscle and brain pathology and vascular physiology, mitochondrial angiopathy, or endothelial dysfunction, were proposed to play an important role for developing stroke-like episodes. Based on a hypothesis of mitochondrial angiopathy theory, we use L-arginine in MELAS patients and report its usefulness. This review aims to give a general idea on the actual knowledge about the possible pathogenic mechanism of stroke-like episodes, including clinical symptoms that lead to stroke-like episodes, muscle, or brain pathology, molecular cellular functions, neuroimagings including MRI, MRS, and SPECT, and the proposed site of action of L-arginine therapy on MELAS patients. Currently, L-arginine therapy may be the most promising for the treatment of stroke-like episodes in MELAS.

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“…Thus, the A14G mutant may not function correctly with tRNA processing and maturation enzymes, and accordingly, defects have been observed in a variety of biochemical pathways (Jacobs and Holt 2000;Florentz 2002;. Cellular studies investigating the A3243G mutant have revealed deficiencies in RNA processing (Masucci and Schon 1996;Rossmanith and Karwan 1998;Koga et al 2003), aminoacylation (El Meziane et al 1998;Janssen et al 1999;Borner et al 2000;Chomyn et al 2000;Wittenhagen and Kelley 2002;Park et al 2003), post-transcriptional tRNA modifi-cation (Helm et al 1999;Yasukawa et al 2000), and translation (Chomyn et al 1992;King et al 1992;Schon et al 1992;Flierl et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Structural probing of a pathogenic tRNA dimer

Roy

Wittenhagen²,

Kelley³

2005

RNA

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The A3243G mutation within the human mitochondrial (hs mt) tRNA Leu(UUR) gene is associated with maternally inherited deafness and diabetes (MIDD) and other mitochondrial encephalopathies. One of the most pronounced structural effects of this mutation is the disruption of the native structure through stabilization of a high-affinity dimeric complex. We conducted a series of studies that address the structural properties of this tRNA dimer, and we assessed its formation under physiological conditions. Enzymatic probing was used to directly define the dimeric interface for the complex, and a discrete region of the D-stem and loop of hs mt tRNA Leu(UUR) was identified. The dependence of dimerization on magnesium ions and temperature was also tested. The formation of the tRNA dimer is influenced by temperature, with dimerization becoming more efficient at physiological temperature. Complexation of the mutant tRNA is also affected by the amount of magnesium present, and occurs at concentrations present intracellularly. Terbium probing experiments revealed a specific metal ion-binding site localized at the site of the A3243G mutation that is unique to the dimer structure. This metal ion-binding site presents a striking parallel to dimeric complexes of viral RNAs, which use the same hexanucleotide sequence for complexation and feature a similarly positioned metal ion-binding site within the dimeric structure. Taken together, these results indicate that the unique dimeric complex formed by the hs mt tRNA Leu(UUR) A3243G mutant exhibits interesting similarities to biological RNA dimers, and may play a role in the loss of function caused by this mutation in vivo.

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Increased mitochondrial processing intermediates associated with three tRNALeu(UUR) gene mutations

Cited by 24 publications

References 9 publications

Molecular dysfunction associated with the human mitochondrial 3302A>G mutation in the MTTL1 (mt-tRNALeu(UUR)) gene

Molecular dysfunction associated with the human mitochondrial 3302A>G mutation in the MTTL1 (mt-tRNALeu(UUR)) gene

MELAS and l‐arginine therapy: pathophysiology of stroke‐like episodes

Structural probing of a pathogenic tRNA dimer

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