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High levels of TFAM repress mammalian mitochondrial DNA transcription in vivo

Mitochondrial transcription factor A (TFAM) is compacting mitochondrial DNA (dmtDNA) into nucleoids and directly controls mtDNA copy number. Here, we show that the TFAM-to-mtDNA ratio is critical for maintaining normal mtDNA expression in different mouse tissues. Moderately increased TFAM protein le...

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Main Authors: Bonekamp, Nina A. (Author) , Jiang, Min (Author) , Motori, Elisa (Author) , Villegas, Rodolfo Garcia (Author) , Koolmeister, Camilla (Author) , Atanassov, Ilian (Author) , Mesaros, Andrea (Author) , Park, Chan Bae (Author) , Larsson, Nils-Göran (Author)
Format: Article (Journal)
Language:English
Published: 30 August, 2021
In: Life science alliance
Year: 2021, Volume: 4, Issue: 11, Pages: 1-17
ISSN:2575-1077
DOI:10.26508/lsa.202101034
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.26508/lsa.202101034
Verlag, lizenzpflichtig, Volltext: https://www.life-science-alliance.org/content/4/11/e202101034
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Author Notes:Nina A. Bonekamp, Min Jiang, Elisa Motori, Rodolfo Garcia Villegas, Camilla Koolmeister, Ilian Atanassov, Andrea Mesaros, Chan Bae Park, Nils-Göran Larsson
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Summary:Mitochondrial transcription factor A (TFAM) is compacting mitochondrial DNA (dmtDNA) into nucleoids and directly controls mtDNA copy number. Here, we show that the TFAM-to-mtDNA ratio is critical for maintaining normal mtDNA expression in different mouse tissues. Moderately increased TFAM protein levels increase mtDNA copy number but a normal TFAM-to-mtDNA ratio is maintained resulting in unaltered mtDNA expression and normal whole animal metabolism. Mice ubiquitously expressing very high TFAM levels develop pathology leading to deficient oxidative phosphorylation (OXPHOS) and early postnatal lethality. The TFAM-to-mtDNA ratio varies widely between tissues in these mice and is very high in skeletal muscle leading to strong repression of mtDNA expression and OXPHOS deficiency. In the heart, increased mtDNA copy number results in a near normal TFAM-to-mtDNA ratio and maintained OXPHOS capacity. In liver, induction of LONP1 protease and mitochondrial RNA polymerase expression counteracts the silencing effect of high TFAM levels. TFAM thus acts as a general repressor of mtDNA expression and this effect can be counterbalanced by tissue-specific expression of regulatory factors.
Item Description:Published online: 30 August, 2021
Gesehen am 12.01.2023
Physical Description:Online Resource
ISSN:2575-1077
DOI:10.26508/lsa.202101034

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