Mitochondrial transcription factor A is necessary for mtDNA maintance and embryogenesis in mice

Larsson, Nils‐Göran; Wang, Jianming; Wilhelmsson, Hans; Oldfors, Anders; Rustin, Pierre; Lewandoski, Mark; Barsh, Gregory S.; Clayton, David A.

doi:10.1038/ng0398-231

Cited by 1,435 publications

(1,219 citation statements)

References 26 publications

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“…S3a,b) led to both mtDNA and mtRNA depletion, and a consequent deficiency in ETC function in the same manner as EtBr treatment (Fig. 4a–c), as described previously 20. In contrast to the pseudo‐ρ0 cells (Fig.…”

Section: Resultssupporting

confidence: 82%

Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

et al. 2016

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Mitochondria are multifunctional organelles; they have been implicated in various aspects of tumorigenesis. In this study, we investigated a novel role of the basal electron transport chain (ETC) activity in cell proliferation by inhibiting mitochondrial replication and transcription (mtR/T) using pharmacological and genetic interventions, which depleted mitochondrial DNA/RNA, thereby inducing ETC deficiency. Interestingly, mtR/T inhibition did not decrease ATP levels despite deficiency in ETC activity in different cell types, including MDA‐MB‐231 breast cancer cells, but it severely impeded cell cycle progression, specifically progression during G2 and/or M phases in the cancer cells. Under these conditions, the expression of a group of cell cycle regulators was downregulated without affecting the growth signaling pathway. Further analysis suggested that the transcriptional network organized by E2F1 was significantly affected because of the downregulation of E2F1 in response to ETC deficiency, which eventually resulted in the suppression of cell proliferation. Thus, in this study, the E2F1‐mediated ETC‐dependent mechanism has emerged as the regulatory mechanism of cell cycle progression. In addition to E2F1, FOXM1 and BMYB were also downregulated, which contributed specifically to the defects in G2 and/or M phase progression. Thus, ETC‐deficient cancer cells lost their growing ability, including their tumorigenic potential in vivo. ETC deficiency abolished the production of reactive oxygen species (ROS) from the mitochondria and a mitochondria‐targeted antioxidant mimicked the deficiency, thereby suggesting that ETC activity signaled through ROS production. In conclusion, this novel coupling between ETC activity and cell cycle progression may be an important mechanism for coordinating cell proliferation and metabolism.

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Section: Resultssupporting

confidence: 82%

Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

et al. 2016

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“…A high rate of mitochondrial transcription occurs during cleavage of early embryos to meet high-energy demands and may require the new synthesis and transport of nuclearly encoded mitochondrial respiratory chain components (Larsson et al, 1998). Previous studies established that PPRC1 co-activates NRF1 and NRF2 and regulates many genes encoding protein products involved in mitochondrial respiration (Vercauteren et al, 2006(Vercauteren et al, , 2008.…”

Section: Developmental Dynamicsmentioning

confidence: 99%

“…The embryonic lethality of pprc1-null mice in our study was not unexpected, because deficiency of some other key components of the transcription of mitochondrial transcription, such as NRF1, NRF2, and TFAM, also leads to a similar form of early embryonic lethality in mice. This may be due to decreased expression of genes that regulate mitochondrial biogenesis and function (Larsson et al, 1998;Huo and Scarpulla, 2001;Ristevski et al, 2004).…”

Section: Developmental Dynamicsmentioning

confidence: 99%

Peri‐implantation lethality in mice lacking the PGC‐1‐related coactivator protein

Sun

Feng

et al. 2012

Developmental Dynamics

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Background: Members of the PPARg coactivator-1 (PGC-1) family are central transcriptional coactivators that regulate cell metabolic processes ranging from mitochondrial biogenesis to oxidative respiration. PGC-1-related coactivator (PPRC1 or PRC), initially identified as a member of the PGC-1 family, is believed to regulate mitochondria biogenesis, respiration pathways, and cell proliferation. However, its physiological role is not clearly understood. Here, we investigate the biological functions of PPRC1 in vivo using PPRC1 deficient mice generated by gene targeting. Results: Homozygous deficient PPRC1 mice failed to form egg cylinders and died after implantation but before embryonic day 6.5, whereas mice heterozygous for PPRC1 were viable, fertile and indistinguishable from their wild-type littermates. Furthermore, PPRC1 mRNA was expressed at the embryonic stage before implantation and was rapidly upregulated during the first day of embryoid body formation. The PPRC1 mRNA was then subsequently down-regulated, although its precise function at this stage of development was unclear. Conclusions: This is the first study to suggest a nonredundant role for PPRC1 in mouse early embryonic development. Developmental Dynamics 241:975-983, 2012. V C 2012 Wiley Periodicals, Inc.Key words: embryonic lethality; gene targeting; PGC-1-related coactivator; PGC-1 family Key findings:Disruption of pprc1 gene causes peri-implantation embryonic lethality. Developmental deficiencies in pprc1 2/2 embryos occur during peri-implantation. In vitro culturing of pprc1 2/2 blastocysts is susceptible to growth retardation. PPRC1 mRNA is expressed during preimplantation embryonic development. PPRC1 mRNA is rapidly up-regulated during early embryoid body formation. Accepted 23 February 2012Developmental Dynamics ABBREVIATIONS PGC-1 PPARg coactivator-1 PPRC1 PGC-1-a-related coactivator protein BAT brown adipose tissue ICM inner cell mass TG trophoblast giant cells E3.5 embryonic day 3.5 ESC embryonic stem cell EB embryoid body

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“…Studies of knockout mice clarified that TFAM is essential for mtDNA maintenance 9 and that increased transgenic expression of TFAM results in an increase in the number of mtDNA copies in vivo 10 . Confocal microscopy studies have found that TFAM is distributed in a punctuate pattern within the mitochondrial network, colocalizes with mtDNA and is present in every mitochondrial nucleoid 11 .…”

mentioning

confidence: 99%

TFAM forces mtDNA to make a U-turn

Hällberg

Larsson

2011

Nat Struct Mol Biol

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Mitochondrial transcription factor A is necessary for mtDNA maintance and embryogenesis in mice

Cited by 1,435 publications

References 26 publications

Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

Peri‐implantation lethality in mice lacking the PGC‐1‐related coactivator protein

TFAM forces mtDNA to make a U-turn

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