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

Kühl, Inge; Miranda, María; Posse, Viktor; Milenkovic, Dusanka; Mourier, Arnaud; Siira, Stefan J.; Bonekamp, Nina A.; Neumann, Ulla; Filipovska, Aleksandra; Polosa, Paola Loguercio; Gustafsson, Claes M.; Larsson, Nils‐Göran

doi:10.1126/sciadv.1600963

Cited by 101 publications

(101 citation statements)

References 72 publications

(131 reference statements)

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“…All embryos with the Tefm −/− genotype ( n = 11) were small and lacked heart structure, while embryos with the Tefm +/+ ( n = 10) or Tefm +/− ( n = 22) genotype were well developed with normal appearance typical of E8.5 embryos (Fig B). Thus, loss of TEFM causes severe developmental defects and embryonic lethality at E8.5, consistent with the phenotype of other knockout mice with homozygous disruption of genes critical for mtDNA expression and maintenance .…”

Section: Resultssupporting

confidence: 82%

“…Another interesting finding is that loss of TEFM leads to a dramatic increase of POLRMT levels (Fig E and F) and a mild increase of MRPL12 levels (Fig EV3C). One may argue that MRPL12 binds to and stabilizes POLRMT , but we have failed to confirm this proposed interaction in previous studies . In density gradients with wild‐type mitochondrial extracts, POLRMT is found in fractions containing mtDNA, whereas MRPL12 is present in mtDNA‐free fractions containing other ribosomal proteins , arguing against a significant interaction between MRPL12 and POLRMT.…”

Section: Discussioncontrasting

confidence: 76%

“…One may argue that MRPL12 binds to and stabilizes POLRMT , but we have failed to confirm this proposed interaction in previous studies . In density gradients with wild‐type mitochondrial extracts, POLRMT is found in fractions containing mtDNA, whereas MRPL12 is present in mtDNA‐free fractions containing other ribosomal proteins , arguing against a significant interaction between MRPL12 and POLRMT. Recently, we analyzed the proteome of 5 tissue‐specific knockout mouse mutants with disruption of mtDNA gene expression at different levels and found that the expression of 12S and 16S rRNA was critical for the stability of most mitoribosomal proteins .…”

Section: Discussioncontrasting

confidence: 76%

“…To measure 7S RNA levels in Tefm knockout mice, a 32 P‐radiolabeled RNA probe, corresponding to the first 45 base pairs (bp) of the RNA produced by transcription initiation at LSP, was used for northern blot analyses (Fig B). Samples from tissue‐specific Mterf4 knockouts, which are known to have increased 7S RNA levels, and tissue‐specific Polrmt knockouts, which are known to lack 7S RNA , were included as positive and negative controls, respectively. The levels of 7S RNA were markedly increased in Tefm knockout mice in comparison with controls (Fig B).…”

Section: Resultsmentioning

confidence: 99%

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TEFM regulates both transcription elongation and RNA processing in mitochondria

et al. 2019

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Regulation of replication and expression of mitochondrial DNA (mt DNA ) is essential for cellular energy conversion via oxidative phosphorylation. The mitochondrial transcription elongation factor ( TEFM ) has been proposed to regulate the switch between transcription termination for replication primer formation and processive, near genome‐length transcription for mt DNA gene expression. Here, we report that Tefm is essential for mouse embryogenesis and that levels of promoter‐distal mitochondrial transcripts are drastically reduced in conditional Tefm ‐knockout hearts. In contrast, the promoter‐proximal transcripts are much increased in Tefm knockout mice, but they mostly terminate before the region where the switch from transcription to replication occurs, and consequently, de novo mt DNA replication is profoundly reduced. Unexpectedly, deep sequencing of RNA from Tefm knockouts revealed accumulation of unprocessed transcripts in addition to defective transcription elongation. Furthermore, a proximity‐labeling (Bio ID ) assay showed that TEFM interacts with multiple RNA processing factors. Our data demonstrate that TEFM acts as a general transcription elongation factor, necessary for both gene transcription and replication primer formation, and loss of TEFM affects RNA processing in mammalian mitochondria.

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Section: Resultssupporting

confidence: 82%

Section: Discussioncontrasting

confidence: 76%

Section: Discussioncontrasting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

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TEFM regulates both transcription elongation and RNA processing in mitochondria

et al. 2019

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“…POLRMT has sequence specific binding to TFAM and mtDNA promoter regions as well as upstream regions. This complex encourages binding of mitochondrial transcription factor B2 (TFB2M), resulting in a single RNA precursor in the mitochondrion and is the initiation of transcription (Kühl et al, ). This process further advances to transcription elongation, transcription termination, initiation of translation, and translation elongation ultimately resulting in the synthesis of mature mitochondrial proteins (Taanman, ).…”

Section: Mitochondriamentioning

confidence: 99%

The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy

Theilen

Kunkel

Tyagi

2017

Journal Cellular Physiology

111

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Skeletal muscle atrophy is the consequence of protein degradation exceeding protein synthesis. This arises for a multitude of reasons including the unloading of muscle during microgravity, post-surgery bedrest, immobilization of a limb after injury, and overall disuse of the musculature. The development of therapies prior to skeletal muscle atrophy settings to diminish protein degradation is scarce. Mitochondrial dysfunction is associated with skeletal muscle atrophy and contributes to the induction of protein degradation and cell apoptosis through increased levels of ROS observed with the loss of organelle function. ROS binds mtDNA, leading to its degradation and decreasing functionality. Mitochondrial transcription factor A (TFAM) will bind and coat mtDNA, protecting it from ROS and degradation while increasing mitochondrial function. Exercise stimulates cell signaling pathways that converge on and increase PGC-1α, a well-known activator of the transcription of TFAM and mitochondrial biogenesis. Therefore, in the present review we are proposing, separately, exercise and TFAM treatments prior to atrophic settings (muscle unloading or disuse) alleviate skeletal muscle atrophy through enhanced mitochondrial adaptations and function. Additionally, we hypothesize the combination of exercise and TFAM leads to a synergistic effect in targeting mitochondrial function to prevent skeletal muscle atrophy.

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The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms

2018

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The mitochondrial transcription factor A, or TFAM, is a mitochondrial DNA (mtDNA)‐binding protein essential for genome maintenance. TFAM functions in determining the abundance of the mitochondrial genome by regulating packaging, stability, and replication. More recently, TFAM has been shown to play a central role in the mtDNA stress‐mediated inflammatory response. Emerging evidence indicates that decreased mtDNA copy number is associated with several aging‐related pathologies; however, little is known about the association of TFAM abundance and disease. In this Review, we evaluate the potential associations of altered TFAM levels or mtDNA copy number with neurodegeneration. We also describe potential mechanisms by which mtDNA replication, transcription initiation, and TFAM‐mediated endogenous danger signals may impact mitochondrial homeostasis in Alzheimer, Huntington, Parkinson, and other neurodegenerative diseases.

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

Abstract: Mitochondrial transcription for replication primer formation has priority over gene expression at low POLRMT levels.

Cited by 101 publications

References 72 publications

TEFM regulates both transcription elongation and RNA processing in mitochondria

TEFM regulates both transcription elongation and RNA processing in mitochondria

The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy

The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms

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