scholarly journals Somatic alterations in mitochondrial DNA produce changes in cell growth and metabolism supporting a tumorigenic phenotype

2012 ◽  
Vol 1822 (2) ◽  
pp. 293-300 ◽  
Author(s):  
Jana Jandova ◽  
Mingjian Shi ◽  
Kimberly G. Norman ◽  
George P. Stricklin ◽  
James E. Sligh
Keyword(s):  
Mitochondrial Dna ◽  
Cell Growth ◽  
Somatic Alterations

scholarly journals Investigations of the mechanism by which mammalian cell growth is inhibited by N1N12-bis(ethyl)spermine

1993 ◽  
Vol 291 (1) ◽  
pp. 131-137 ◽  
Author(s):  
L Albanese ◽  
R J Bergeron ◽  
A E Pegg
Keyword(s):  
Mitochondrial Dna ◽  
Cell Growth ◽  
Cell Lines ◽  
Ornithine Decarboxylase ◽  
Polyamine Analogues ◽  
Proliferative Effect ◽  
L1210 Cells ◽  
Inhibition Of Growth ◽  
Variant Cell ◽  
Mammalian Cell Growth

N1N12-Bis(ethyl)spermine (BESM) and related compounds are powerful inhibitors of cell growth that may have potential as anti-neoplastic agents [Bergeron, Neims, McManis, Hawthorne, Vinson, Bortell and Ingeno (1988) J. Med. Chem. 31, 1183-1190]. The mechanism by which these compounds bring about their effects was investigated by using variant cell lines in which processes thought to be altered by these agents are perturbed. Comparisons between the response of these cells and of their parental equivalents to BESM, N1N11-bis(ethyl)norspermine, N1N14-bis(ethyl)homospermine and N1N8-bis(ethyl)spermidine were then made. It was found that D-R cells, an L1210-derived line that over-expresses ornithine decarboxylase, were not resistant to these compounds. This indicates that the decrease in ornithine decarboxylase is not critical for the action of the compounds on cell growth. Furthermore, although polyamine levels were decreased in the D-R cells, the content was not totally depleted, indicating that such depletion is also not essential for the anti-proliferative effect. Two cell lines lacking mitochondrial DNA (human 143B206 cells and chicken DU3 cells) did not differ in sensitivity to BESM from their parental 143BTK- and DU24 cells. Furthermore, the inhibition of respiration in L1210 cells in response to BESM developed more slowly than the inhibition of growth. Thus it appears that the inhibitions of mitochondrial DNA synthesis and of mitochondrial respiration are also not primary factors in the anti-proliferative effects of these polyamine analogues. The inhibition of growth did, however, correlate with the intracellular accumulation of the analogues. It appears that the bis(ethyl)polyamine derivatives act by binding to intracellular target molecules and preventing macromolecular synthesis. The decline in normal polyamines may facilitate such binding, but is not essential for growth arrest.

scholarly journals Effect of cobalt treatment on cell growth and mitochondrial DNA damage in HEK293 acutely exposed to hydrogen peroxide

2006 ◽  
Vol 20 (5) ◽  
Author(s):  
Yasutomo Nomura ◽  
Hiroyuki Fujiwara ◽  
Kohei Ito ◽  
Michihiko Sato ◽  
Eiji Takahashi ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Mitochondrial Dna ◽  
Cell Growth ◽  
Mitochondrial Dna Damage

scholarly journals A Mitochondrial DNA Primase Is Essential for Cell Growth and Kinetoplast DNA Replication in Trypanosoma brucei

2010 ◽  
Vol 30 (6) ◽  
pp. 1319-1328 ◽  
Author(s):  
Jane C. Hines ◽  
Dan S. Ray
Keyword(s):  
Mitochondrial Dna ◽  
Dna Replication ◽  
Cell Growth ◽  
Trypanosoma Brucei ◽  
Dna Polymerase ◽  
Rnase H ◽  
Kinetoplast Dna ◽  
African Trypanosomes ◽  
Dna Primase

ABSTRACT Kinetoplast DNA in African trypanosomes contains a novel form of mitochondrial DNA consisting of thousands of minicircles and dozens of maxicircles topologically interlocked to form a two-dimensional sheet. The replication of this unusual form of mitochondrial DNA has been studied for more than 30 years, and although a large number of kinetoplast replication genes and proteins have been identified, in vitro replication of these DNAs has not been possible since a kinetoplast DNA primase has not been available. We describe here a Trypanosoma brucei DNA primase gene, PRI1, that encodes a 70-kDa protein that localizes to the kinetoplast and is essential for both cell growth and kinetoplast DNA replication. The expression of PRI1 mRNA is cyclic and reaches maximum levels at a time corresponding to duplication of the kinetoplast DNA. A 3′-hydroxyl-terminated oligoriboadenylate is synthesized on a poly(dT) template by a recombinant form of the PRI1 protein and is subsequently elongated by DNA polymerase and added dATP. Poly(dA) synthesis is dependent on both PRI1 protein and ATP and is inhibited by RNase H treatment of the product of PRI1 synthesis.

scholarly journals Mitochondrial DNA copy number variation across human cancers

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ed Reznik ◽  
Martin L Miller ◽  
Yasin Şenbabaoğlu ◽  
Nadeem Riaz ◽  
Judy Sarungbam ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Copy Number Variation ◽  
Copy Number ◽  
The Cancer Genome Atlas ◽  
Mtdna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Number Variation ◽  
Somatic Alterations ◽  
Immunohistochemical Evidence ◽  
Tumor Types

Mutations, deletions, and changes in copy number of mitochondrial DNA (mtDNA), are observed throughout cancers. Here, we survey mtDNA copy number variation across 22 tumor types profiled by The Cancer Genome Atlas project. We observe a tendency for some cancers, especially of the bladder, breast, and kidney, to be depleted of mtDNA, relative to matched normal tissue. Analysis of genetic context reveals an association between incidence of several somatic alterations, including IDH1 mutations in gliomas, and mtDNA content. In some but not all cancer types, mtDNA content is correlated with the expression of respiratory genes, and anti-correlated to the expression of immune response and cell-cycle genes. In tandem with immunohistochemical evidence, we find that some tumors may compensate for mtDNA depletion to sustain levels of respiratory proteins. Our results highlight the extent of mtDNA copy number variation in tumors and point to related therapeutic opportunities.

scholarly journals A High-Order Trans-Membrane Structural Linkage Is Responsible for Mitochondrial Genome Positioning and Segregation by Flagellar Basal Bodies in Trypanosomes

2003 ◽  
Vol 14 (5) ◽  
pp. 1769-1779 ◽  
Author(s):  
Emmanuel O. Ogbadoyi ◽  
Derrick R. Robinson ◽  
Keith Gull
Keyword(s):  
Cell Cycle ◽  
Mitochondrial Dna ◽  
Cell Growth ◽  
Mitochondrial Genome ◽  
S Phase ◽  
High Order ◽  
Basal Bodies ◽  
Kinetoplast Dna ◽  
Mitochondrial Membranes ◽  
Extreme Form

In trypanosomes, the large mitochondrial genome within the kinetoplast is physically connected to the flagellar basal bodies and is segregated by them during cell growth. The structural linkage enabling these phenomena is unknown. We have developed novel extraction/fixation protocols to characterize the links involved in kinetoplast-flagellum attachment and segregation. We show that three specific components comprise a structure that we have termed the tripartite attachment complex (TAC). The TAC involves a set of filaments linking the basal bodies to a zone of differentiated outer and inner mitochondrial membranes and a further set of intramitochondrial filaments linking the inner face of the differentiated membrane zone to the kinetoplast. The TAC and flagellum-kinetoplast DNA connections are sustained throughout the cell cycle and are replicated and remodeled during the periodic kinetoplast DNA S phase. This understanding of the high-order trans-membrane linkage provides an explanation for the spatial position of the trypanosome mitochondrial genome and its mechanism of segregation. Moreover, the architecture of the TAC suggests that it may also function in providing a structural and vectorial role during replication of this catenated mass of mitochondrial DNA. We suggest that this complex may represent an extreme form of a more generally occurring mitochondrion/cytoskeleton interaction.

scholarly journals Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth

2021 ◽  
Author(s):  
Anika Seel ◽  
Francesco Padovani ◽  
Alissa Finster ◽  
Moritz Mayer ◽  
Daniela Bureik ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mitochondrial Dna ◽  
Dna Replication ◽  
Cell Growth ◽  
Cell Volume ◽  
Nuclear Dna ◽  
Limiting Factors ◽  
G1 Arrest ◽  
Mitochondrial Dna Copy Number ◽  
Dna Maintenance

AbstractTo maintain stable DNA concentrations, proliferating cells need to coordinate DNA replication with cell growth. For nuclear DNA, eukaryotic cells achieve this by coupling DNA replication to cell cycle progression, ensuring that DNA is doubled exactly once per cell cycle. By contrast, mitochondrial DNA replication is typically not strictly coupled to the cell cycle, leaving the open question of how cells maintain the correct amount of mitochondrial DNA during cell growth. Here, we show that in budding yeast, mitochondrial DNA copy number increases with cell volume, both in asynchronously cycling populations and during G1 arrest. Our findings suggest that cell-volume-dependent mitochondrial DNA maintenance is achieved through nuclear encoded limiting factors, including the mitochondrial DNA polymerase Mip1 and the packaging factor Abf2, whose amount increases in proportion to cell volume. By directly linking mitochondrial DNA maintenance to nuclear protein synthesis, and thus cell growth, constant mitochondrial DNA concentrations can be robustly maintained without a need for cell-cycle-dependent regulation.

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