+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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

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

Human Molecular Genetics 24(25): 7286-7294

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.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 058486578

Download citation: RISBibTeXText

PMID: 26464487

DOI: 10.1093/hmg/ddv427

Related references

NSUN4 is a dual function mitochondrial protein required for both methylation of 12S rRNA and coordination of mitoribosomal assembly. Plos Genetics 10(2): E1004110, 2014

Impact of catechol-O-methyltransferase (COMT) gene polymorphism on promoter methylation status in gastric mucosa. Anticancer Research 29(7): 2857-2861, 2009

Maternal inheritance of the mouse mitochondrial genome is not mediated by a loss or gross alteration of the paternal mitochondrial DNA or by methylation of the oocyte mitochondrial DNA. Developmental Biology 102(2): 452-461, 1984

DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. Carcinogenesis 27(6): 1160-1168, 2006

Mutational screening of the mitochondrial transcription factors B1 and B2 (TFB1M and TFB2M) in Parkinson's disease. Parkinsonism and Related Disorders 15(6): 468-470, 2008

Loss of TFB1M results in mitochondrial dysfunction that leads to impaired insulin secretion and diabetes. Human Molecular Genetics 23(21): 5733-5749, 2015

Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Annual Review of Pharmacology and Toxicology 39: 19-52, 1999

Mitochondrial DNA depletion and its correlation with TFAM, TFB1M, TFB2M and POLG in human diffusely infiltrating astrocytomas. Mitochondrion 11(1): 48-53, 2011

Structural insight into maintenance methylation by mouse DNA methyltransferase 1. Acta Crystallographica Section A Foundations of Crystallography 67(A1): C285-C285, 2011

The methylation status of the gene for O6-methylguanine-DNA methyltransferase in human Mer+ and Mer- cells. Carcinogenesis 16(8): 1857-1863, 1995

DNA methylation status of nuclear-encoded mitochondrial genes underlies the tissue-dependent mitochondrial functions. Bmc Genomics 11: 481, 2010

Structural insight into maintenance methylation by mouse DNA methyltransferase 1 (Dnmt1). Proceedings of the National Academy of Sciences of the United States of America 108(22): 9055-9059, 2011

Processive methylation of hemimethylated CpG sites by mouse Dnmt1 DNA methyltransferase. Journal of Biological Chemistry 280(1): 64-72, 2004

De novo and maintenance DNA methylation by a mouse plasmacytoma cell DNA methyltransferase. Journal of Biological Chemistry 263(9): 4392-4399, 1988

Processive Methylation of Hemimethylated CpG Sites by Mouse Dnmtl DNA Methyltransferase. The Journal of Biological Chemistry 280(1): 72, 2005