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Metodiev, Metodi D.,Lesko, Nicole,Park, Chan Bae,Cá,mara, Yolanda,Shi, Yonghong,Wibom, Rolf,Hultenby, Kjell,Gustafsson, Claes M.,Larsson, Nils-Gö,ran Elsevier 2009 Cell metabolism Vol.9 No.4
<P><B>Summary</B></P><P>The 3′ end of the rRNA of the small ribosomal subunit contains two extremely highly conserved dimethylated adenines. This modification and the responsible methyltransferases are present in all three domains of life, but its function has remained elusive. We have disrupted the mouse <I>Tfb1m</I> gene encoding a mitochondrial protein homologous to bacterial dimethyltransferases and demonstrate here that loss of TFB1M is embryonic lethal. Disruption of <I>Tfb1m</I> in heart leads to complete loss of adenine dimethylation of the rRNA of the small mitochondrial ribosomal subunit, impaired assembly of the mitochondrial ribosome, and abolished mitochondrial translation. In addition, we present biochemical evidence that TFB1M does not activate or repress transcription in the presence of TFB2M. Our results thus show that TFB1M is a nonredundant dimethyltransferase in mammalian mitochondria. In addition, we provide a possible explanation for the universal conservation of adenine dimethylation of rRNA by showing a critical role in ribosome maintenance.</P>
Maintenance of respiratory chain function in mouse hearts with severely impaired mtDNA transcription
Freyer, Christoph,Park, Chan Bae,Ekstrand, Mats I.,Shi, Yonghong,Khvorostova, Julia,Wibom, Rolf,Falkenberg, Maria,Gustafsson, Claes M.,Larsson, Nils-Gö,ran Oxford University Press 2010 Nucleic acids research Vol.38 No.19
<P>The basal mitochondrial transcription machinery is essential for biogenesis of the respiratory chain and consists of mitochondrial RNA polymerase, mitochondrial transcription factor A (TFAM) and mitochondrial transcription factor B2. This triad of proteins is sufficient and necessary for mtDNA transcription initiation. Abolished mtDNA transcription caused by tissue-specific knockout of TFAM in the mouse heart leads to early onset of a severe mitochondrial cardiomyopathy with lethality within the first post-natal weeks. Here, we describe a mouse model expressing human TFAM instead of the endogenous mouse TFAM in heart. These rescue mice have severe reduction in mtDNA transcription initiation, but, surprisingly, are healthy at the age of 52 weeks with near-normal steady-state levels of transcripts. In addition, we demonstrate that heavy-strand mtDNA transcription normally terminates at the termination-associated sequence in the control region. This termination is abolished in rescue animals resulting in heavy (H)-strand transcription of the entire control region. In conclusion, we demonstrate here the existence of an unexpected mtDNA transcript stabilization mechanism that almost completely compensates for the severely reduced transcription initiation in rescue hearts. Future elucidation of the underlying molecular mechanism may provide a novel pathway to treat mitochondrial dysfunction in human pathology.</P>