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POLRMT regulates the switch between replication primer formation and gene expression of mammalian mtDNA

Journal article
Authors I. Kuhl
M. Miranda
Viktor Posse
D. Milenkovic
A. Mourier
S. J. Siira
N. A. Bonekamp
U. Neumann
A. Filipovska
P. L. Polosa
Claes M Gustafsson
N. G. Larsson
Published in Science Advances
Volume 2
Issue 8
ISSN 2375-2548
Publication year 2016
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Language en
Keywords mitochondrial rna-polymerase, transcription factor-a, mouse l-cells, dna-replication, activate transcription, heavy-strand, lon protease, copy number, d-loop, initiation, Science & Technology - Other Topics, ang dd, 1985, embo journal, v4, p1559, ang dd, 1984, cell, v36, p635, ang dd, 1985, proceedings of the national academy of sciences of the united states of america, v82, p351
Subject categories Cell and Molecular Biology


Mitochondria are vital in providing cellular energy via their oxidative phosphorylation system, which requires the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes (mtDNA). Transcription of the circular mammalian mtDNA depends on a single mitochondrial RNA polymerase (POLRMT). Although the transcription initiation process is well understood, it is debated whether POLRMT also serves as the primase for the initiation of mtDNA replication. In the nucleus, the RNA polymerases needed for gene expression have no such role. Conditional knockout of Polrmt in the heart results in severe mitochondrial dysfunction causing dilated cardiomyopathy in young mice. We further studied the molecular consequences of different expression levels of POLRMT and found that POLRMT is essential for primer synthesis to initiate mtDNA replication in vivo. Furthermore, transcription initiation for primer formation has priority over gene expression. Surprisingly, mitochondrial transcription factor A (TFAM) exists in an mtDNA-free pool in the Polrmt knockout mice. TFAM levels remain unchanged despite strong mtDNA depletion, and TFAM is thus protected from degradation of the AAA(+) Lon protease in the absence of POLRMT. Last, we report that mitochondrial transcription elongation factor may compensate for a partial depletion of POLRMT in heterozygous Polrmt knockout mice, indicating a direct regulatory role of this factor in transcription. In conclusion, we present in vivo evidence that POLRMT has a key regulatory role in the replication of mammalian mtDNA and is part of a transcriptional mechanism that provides a switch between primer formation for mtDNA replication and mitochondrial gene expression.

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