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TFB1M - Insights into sensorineural deafness

Source: GMC


Sensorineural deafness can be caused by mitochondrial dysfunction and several causative mutations in mitochondrial DNA as well as in mitochondrial translation have been described. However, the pathomechanisms are yet not fully understood. The A1555G mutation in the mitochondrial 12S rRNA gene causes sensorineural deafness to various degrees suggesting the influence of modifying events. Recently it was proposed that hypermethylation of specific adenosines in the 12S rRNA is the key to the pathophysiology of the deafness. To revisit this hypothesis Seungmin Lee and colleagues investigated mice overexpressing the mitochondrial methyltransferase TFB1M which is postulated to induce mitoribosomal hypermethylation and deafness as a consequence. TFB1M belongs to a family of highly conserved adenosine dimethyltransferases found in bacteria, archaea and eukaryotes and  which are essential for mitoribosomal biogenesis.

The scientists reevaluated the 12S rRNA methylation status as well as the hearing sensitivity in those transgenic mice.

In the German Mouse Clinic the mice were tested for Auditory Brainstem Response (ABR). In contrast to the previous results, no increase in hearing thresholds at higher frequencies has been detected. The overexpression of TFB1m also had no influence on the general age-related decline in hearing sensitivity. In addition, the authors showed that already high 12S rRNA methylation levels were not further increased by the overexpression of TFB1M.
The authors conclude that therapies directed against mitoribosomal methylation are unlikely to be beneficial to patients with sensorineural hearing loss or other types of mitochondrial disease.

Seungmin Lee, Simon Rose, Metodi D. Metodiev, Lore Becker, Alexandra Vernaleken, Thomas Klopstock, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě De Angelis, Stephen Douthwaite and Nils-Göran Larsson, (2015): Overexpression of the mitochondrial methyltransferase TFB1M in the mouse does not impact mitoribosomal methylation status or hearing. Human Molecular Genetics, Vol. 24, No. 25 7286–7294