Mechanism of mammalian mitochondrial DNA replication: import of mitochondrial transcription factor A into isolated mitochondria stimulates 7S DNA synthesis

Gensler, Sven; Weber, Katharina; Schmitt, Wolfgang; Pérez‐Martos, Acisclo; Enríquez, José Antonio; Montoya, Julio; Wiesner, Rudolf J.

doi:10.1093/nar/29.17.3657

Cited by 62 publications

(55 citation statements)

References 26 publications

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“…Because CV values are very similar at the G3 and G4 stages for embryos produced by the two procedures, one hypothesis which might explain increased levels of donor cell heteroplasmy in the initial stages of NT-F embryo development would be that somatic mitochondria may be able to replicate during the initial phases of embryo development independent of embryonic control, because these mitochondria may have brought essential enzymes with them from the somatic cells (Gensler et al, 2001;Wiedemann et al, 2004). This replication could explain the greater quantity of mtDNA in the fourth stage (G4) of embryo development.…”

Section: Discussionmentioning

confidence: 99%

The Kinetics of Donor Cell mtDNA in Embryonic and Somatic Donor Cell-Derived Bovine Embryos

Ferreira

Meirelles²,

Yamazaki

et al. 2007

Cloning and Stem Cells

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The mechanisms controlling the outcome of donor cell-derived mitochondrial DNA (mtDNA) in cloned animals remain largely unknown. This research was designed to investigate the kinetics of somatic and embryonic mtDNA in reconstructed bovine embryos during preimplantation development, as well as in cloned animals. The experiment involved two different procedures of embryo reconstruction and their evaluation at five distinct phases of embryo development to measure the proportion of donor cell mtDNA (Bos indicus), as well as the segregation of this mtDNA during cleavage. The ratio of donor cell (B. indicus) to host oocyte (B. taurus) mtDNA (heteroplasmy) from blastomere-(NT-B) and fibroblast-(NT-F) reconstructed embryos was estimated using an allele-specific PCR with fluorochrome-stained specific primers in each sampled blastomere, in whole blastocysts, and in the tissues of a fibroblast-derived newborn clone. NT-B zygotes and blastocysts show similar levels of heteroplasmy (11.0% and 14.0%, respectively), despite a significant decrease at the 9-16 cell stage (5.8%; p Ͻ 0.05). Heteroplasmy levels in NT-F reconstructed zygotes, however, increased from an initial low level (4.7%), to 12.9% (p Ͻ 0.05) at the 9-16 cell stage. The NT-F blastocysts contained low levels of heteroplasmy (2.2%) and no somatic-derived mtDNA was detected in the gametes or the tissues of the newborn calf cloned. These results suggest that, in contrast to the mtDNA of blastomeres, that of somatic cells either undergoes replication or escapes degradation during cleavage, although it is degraded later after the blastocyst stage or lost during somatic development, as revealed by the lack of donor cell mtDNA at birth.

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Section: Discussionmentioning

confidence: 99%

The Kinetics of Donor Cell mtDNA in Embryonic and Somatic Donor Cell-Derived Bovine Embryos

Ferreira

Meirelles²,

Yamazaki

et al. 2007

Cloning and Stem Cells

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“…These experiments clearly underlined the vital importance of this protein, however, they could not distinguish between the two possible TFAM roles in mtDNA maintenance, namely its involvement in replication initiation vs. mtDNA binding. We have shown that import of TFAM into isolated mitochondria stimulates the rate of transcription and initiates synthesis of DNA [27,28] and that overexpression in HeLa and HEK cells increases mitochondrial transcript levels, but is not sufficient to increase mtDNA copy number [29], emphasizing its role in transcription regulation in situ. The concentration of TFAM and mtDNA was measured in mitochondria from human placenta [30] and mouse kidney [31] and the authors found enough TFAM to completely cover all mtDNA molecules.…”

Section: Organization Transcription and Replication Of Mtdnamentioning

confidence: 98%

Mitochondrial DNA damage and the aging process–facts and imaginations

Wiesner

Kunz

2006

Free Radical Research

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Mitochondrial DNA (mtDNA) is a circular double-stranded molecule organized in nucleoids and covered by the histone-like protein mitochondrial transcription factor A (TFAM). Even though mtDNA repair capacity appears to be adequate the accumulation of mtDNA mutations has been shown to be at least one important molecular mechanism of human aging. Reactive oxygen species (ROS), which are generated at the FMN moiety of mitochondrial respiratory chain (RC) complex I, should be considered to be important at least for the generation of age-dependent mtDNA deletions. However, the accumulation of acquired mutations to functionally relevant levels in aged tissues seems to be a consequence of clonal expansions of single founder molecules and not of ongoing mutational events.

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“…However, it is not known if a specific initiation event is required for DNA replication, perhaps guided by a given factor (Shadel & Clayton, 1997). mtTFA could be involved in this process since this protein seems to be required, particularly for L-strand transcription initiation, and the heterozygous knock-out mice for this factor show reduced mtDNA levels (Larsson et al 1998;Gensler et al 2001). A second point of possible regulation is the cleavage of nascent RNAs for primer formation.…”

Section: Regulation Of Mtdna Expressionmentioning

confidence: 99%

Replication and Transcription of Mammalian Mitochondrial Dna

Fernández‐Silva¹,

Enrı́quez

Montoya

2003

Experimental Physiology

355

267

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Mitochondria are subcellular organelles, devoted mainly to energy production in the form of ATP, that contain their own genetic system. Mitochondrial DNA codifies a small, but essential number of polypeptides of the oxidative phosphorylation system. The mammalian mitochondrial genome is an example of extreme economy showing a compact gene organization. The coding sequences for two ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs) and 13 polypeptides are contiguous and without introns. The tRNAs are regularly interspersed between the rRNA and protein‐coding genes, playing a crucial role in RNA maturation from the polycistronic transcripts. A single major non‐coding region, called the D‐loop region, contains the main regulatory sequences for transcription and replication initiation. This genetic organization has its precise correspondence in the mode of expression and distinctive structural features of the RNAs. The basic mechanisms of mitochondrial DNA transcription and replication and the main cis‐acting elements playing a role in both processes have been determined. Many trans‐acting factors involved in mitochondrial gene expression, including the RNA and DNA polymerases, have been cloned or identified. However, the regulatory mechanisms participating in mitochondrial gene expression are still poorly understood. The interest to complete this knowledge is increased by the involvement of mitochondria in human diseases, in basic processes such as heat production, Ca2+ homeostasis and apoptosis, and by their potential role in ageing and carcinogenesis.

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Mechanism of mammalian mitochondrial DNA replication: import of mitochondrial transcription factor A into isolated mitochondria stimulates 7S DNA synthesis

Cited by 62 publications

References 26 publications

The Kinetics of Donor Cell mtDNA in Embryonic and Somatic Donor Cell-Derived Bovine Embryos

The Kinetics of Donor Cell mtDNA in Embryonic and Somatic Donor Cell-Derived Bovine Embryos

Mitochondrial DNA damage and the aging process–facts and imaginations

Replication and Transcription of Mammalian Mitochondrial Dna

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