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Lee, S.* ; Rose, S.* ; Metodiev, M.D.* ; Becker, L. ; Vernaleken, A. ; Klopstock, T.* ; Gailus-Durner, V. ; Fuchs, H. ; Hrabě de Angelis, M. ; Douthwaite, S.* ; Larsson, N.-G.*

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

Hum. Mol. Genet. 24, 7286-7294 (2015)
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Mitochondrial dysfunction is a well-established cause of sensorineural deafness, but the pathophysiological events are poorly understood. 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. The pathophysiology induced by mtDNA mutations has traditionally been attributed to deficient oxidative phosphorylation, which causes energy crisis with functional impairment of multiple cellular processes. 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. In support for this concept, it was reported that overexpression of the essential mitochondrial methyltransferase TFB1M in the mouse was sufficient to induce mitoribosomal hypermethylation and deafness. At variance with this model, we show here that 12S rRNA is near fully methylated in vivo in the mouse and thus cannot be further methylated to any significant extent. Furthermore, bacterial artificial chromosome transgenic mice overexpressing TFB1M have no increase of 12S rRNA methylation levels and hear normally. 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.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Quellenangaben Volume: 24, Issue: 25, Pages: 7286-7294 Article Number: , Supplement: ,
Publisher Oxford University Press
Reviewing status Peer reviewed