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Overexpression of the mitochondrial methyltransferase TFB1M in the mouse does not impact mitoribosomal methylation status or hearing.

Lee S, Rose S, Metodiev MD, Becker L, Vernaleken A, Klopstock T, Gailus-Durner V, Fuchs H, Hrabě De Angelis M, Douthwaite S, Larsson NG - Hum. Mol. Genet. (2015)

Bottom Line: Non-syndromic deafness and predisposition to aminoglycoside-induced deafness can be caused by specific mutations in the 12S rRNA gene of mtDNA and are thus maternally inherited traits.In contrast, it was recently reported that signaling induced by 'hypermethylation' of two conserved adenosines of 12S rRNA in the mitoribosome is of key pathophysiological importance in sensorineural deafness.We thus conclude that therapies directed against mitoribosomal methylation are unlikely to be beneficial to patients with sensorineural hearing loss or other types of mitochondrial disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden.

No MeSH data available.


Related in: MedlinePlus

Nucleotide sequence and predicted structure of the penultimate (helix 44) and ultimate (helix 45) stem-loops at the 3′-end of the mouse mitochondrial 12S rRNA. Variant nucleotides in the highly similar human 12S rRNA sequence are shown (red boxes). The sites of nucleotide dimethylation (helix 45 loop) and nucleotide substitutions implicated in deafness (helix 44) are indicated using the arcane nucleotide numbering systems for the mouse (Mm, black) and human (Hs, red) structures, together with the standard bacterial rRNA numbers from E. coli (Ec, blue). The binding site of aminoglycosides within the decoding region of helix 44 overlaps the human nucleotides 1494 and 1555 linked to deafness and can be seen to be at a structurally distinct location from the dimethylated adenosines (1583/1584 in human; 1006/1007 in mouse). The Cy5-labeled DNA primer (green) was used in primer extension assays to determine the methylation status of these two adenosines in mouse 12S rRNA and hybridizes to the region shown. The Mm and Hs helix 44 structures extend a further 48 nucleotides (48n).
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DDV427F1: Nucleotide sequence and predicted structure of the penultimate (helix 44) and ultimate (helix 45) stem-loops at the 3′-end of the mouse mitochondrial 12S rRNA. Variant nucleotides in the highly similar human 12S rRNA sequence are shown (red boxes). The sites of nucleotide dimethylation (helix 45 loop) and nucleotide substitutions implicated in deafness (helix 44) are indicated using the arcane nucleotide numbering systems for the mouse (Mm, black) and human (Hs, red) structures, together with the standard bacterial rRNA numbers from E. coli (Ec, blue). The binding site of aminoglycosides within the decoding region of helix 44 overlaps the human nucleotides 1494 and 1555 linked to deafness and can be seen to be at a structurally distinct location from the dimethylated adenosines (1583/1584 in human; 1006/1007 in mouse). The Cy5-labeled DNA primer (green) was used in primer extension assays to determine the methylation status of these two adenosines in mouse 12S rRNA and hybridizes to the region shown. The Mm and Hs helix 44 structures extend a further 48 nucleotides (48n).

Mentions: Sensorineural impairment of hearing is a common symptom in patients with reduced mitochondrial translation and can be caused by point mutations in the mitochondrial-encoded tRNA or rRNA genes (1). For example, the m.1555A>G mutation in the gene for the small ribosomal subunit 12S rRNA (corresponding to nucleotide 1490 in helix 44 of 16S rRNA, using the standard Escherichia coli numbering system) is typically homoplasmic with a prevalence of ∼1:500 in European children and adults (4,5) and predisposes patients to hearing loss after treatment with aminoglycosides (Fig. 1) (6,7). The m.1555A>G mutation can also cause maternally inherited deafness (a.k.a. non-syndromic deafness) without previous exposure to antibiotics (6,8,9). A second mutation at m.1494C>T (nucleotide 1410 in E. coli) on the opposite side of helix 44 (Fig. 1) has been reported in other families with maternally inherited non-syndromic deafness (10). The equivalent nucleotides in bacterial 16S rRNA form part of the decoding sequence where aminoglycoside antibiotics bind to perturb the accuracy of protein synthesis (Fig. 1) (11). Chimeric ribosomes displaying the 12S rRNA-decoding sequence within bacterial 16S rRNA become hypersensitive to aminoglycosides when the m.1494C>T and m.1555A>G mutations are introduced (12,13), supporting the view that the ototoxic side effects of aminoglycosides in mitochondria are directly linked to their disruption of ribosome function (12,13).Figure 1.


Overexpression of the mitochondrial methyltransferase TFB1M in the mouse does not impact mitoribosomal methylation status or hearing.

Lee S, Rose S, Metodiev MD, Becker L, Vernaleken A, Klopstock T, Gailus-Durner V, Fuchs H, Hrabě De Angelis M, Douthwaite S, Larsson NG - Hum. Mol. Genet. (2015)

Nucleotide sequence and predicted structure of the penultimate (helix 44) and ultimate (helix 45) stem-loops at the 3′-end of the mouse mitochondrial 12S rRNA. Variant nucleotides in the highly similar human 12S rRNA sequence are shown (red boxes). The sites of nucleotide dimethylation (helix 45 loop) and nucleotide substitutions implicated in deafness (helix 44) are indicated using the arcane nucleotide numbering systems for the mouse (Mm, black) and human (Hs, red) structures, together with the standard bacterial rRNA numbers from E. coli (Ec, blue). The binding site of aminoglycosides within the decoding region of helix 44 overlaps the human nucleotides 1494 and 1555 linked to deafness and can be seen to be at a structurally distinct location from the dimethylated adenosines (1583/1584 in human; 1006/1007 in mouse). The Cy5-labeled DNA primer (green) was used in primer extension assays to determine the methylation status of these two adenosines in mouse 12S rRNA and hybridizes to the region shown. The Mm and Hs helix 44 structures extend a further 48 nucleotides (48n).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4664167&req=5

DDV427F1: Nucleotide sequence and predicted structure of the penultimate (helix 44) and ultimate (helix 45) stem-loops at the 3′-end of the mouse mitochondrial 12S rRNA. Variant nucleotides in the highly similar human 12S rRNA sequence are shown (red boxes). The sites of nucleotide dimethylation (helix 45 loop) and nucleotide substitutions implicated in deafness (helix 44) are indicated using the arcane nucleotide numbering systems for the mouse (Mm, black) and human (Hs, red) structures, together with the standard bacterial rRNA numbers from E. coli (Ec, blue). The binding site of aminoglycosides within the decoding region of helix 44 overlaps the human nucleotides 1494 and 1555 linked to deafness and can be seen to be at a structurally distinct location from the dimethylated adenosines (1583/1584 in human; 1006/1007 in mouse). The Cy5-labeled DNA primer (green) was used in primer extension assays to determine the methylation status of these two adenosines in mouse 12S rRNA and hybridizes to the region shown. The Mm and Hs helix 44 structures extend a further 48 nucleotides (48n).
Mentions: Sensorineural impairment of hearing is a common symptom in patients with reduced mitochondrial translation and can be caused by point mutations in the mitochondrial-encoded tRNA or rRNA genes (1). For example, the m.1555A>G mutation in the gene for the small ribosomal subunit 12S rRNA (corresponding to nucleotide 1490 in helix 44 of 16S rRNA, using the standard Escherichia coli numbering system) is typically homoplasmic with a prevalence of ∼1:500 in European children and adults (4,5) and predisposes patients to hearing loss after treatment with aminoglycosides (Fig. 1) (6,7). The m.1555A>G mutation can also cause maternally inherited deafness (a.k.a. non-syndromic deafness) without previous exposure to antibiotics (6,8,9). A second mutation at m.1494C>T (nucleotide 1410 in E. coli) on the opposite side of helix 44 (Fig. 1) has been reported in other families with maternally inherited non-syndromic deafness (10). The equivalent nucleotides in bacterial 16S rRNA form part of the decoding sequence where aminoglycoside antibiotics bind to perturb the accuracy of protein synthesis (Fig. 1) (11). Chimeric ribosomes displaying the 12S rRNA-decoding sequence within bacterial 16S rRNA become hypersensitive to aminoglycosides when the m.1494C>T and m.1555A>G mutations are introduced (12,13), supporting the view that the ototoxic side effects of aminoglycosides in mitochondria are directly linked to their disruption of ribosome function (12,13).Figure 1.

Bottom Line: Non-syndromic deafness and predisposition to aminoglycoside-induced deafness can be caused by specific mutations in the 12S rRNA gene of mtDNA and are thus maternally inherited traits.In contrast, it was recently reported that signaling induced by 'hypermethylation' of two conserved adenosines of 12S rRNA in the mitoribosome is of key pathophysiological importance in sensorineural deafness.We thus conclude that therapies directed against mitoribosomal methylation are unlikely to be beneficial to patients with sensorineural hearing loss or other types of mitochondrial disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden.

No MeSH data available.


Related in: MedlinePlus