The regulation of mitochondrial DNA copy number in glioblastoma cells

Dickinson, A., Yeung, K. Y., Donoghue, J., Baker, M. J., Kelly, R. D., McKenzie, M., Johns, T. G. and St John, J. C. 2013, The regulation of mitochondrial DNA copy number in glioblastoma cells, Cell death & differentiation, vol. 20, no. 12, pp. 1644-1653, doi: 10.1038/cdd.2013.115.

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Title The regulation of mitochondrial DNA copy number in glioblastoma cells
Author(s) Dickinson, A.
Yeung, K. Y.
Donoghue, J.
Baker, M. J.
Kelly, R. D.
McKenzie, M.ORCID iD for McKenzie, M.
Johns, T. G.
St John, J. C.
Journal name Cell death & differentiation
Volume number 20
Issue number 12
Start page 1644
End page 1653
Total pages 10
Publisher Nature Publishing Group
Place of publication London, Eng.
Publication date 2013-12
ISSN 1350-9047
Keyword(s) Animals
Biomarkers, Tumor
Brain Neoplasms
Cell Differentiation
Cell Line, Tumor
Cell Nucleus
Cell Respiration
DNA Copy Number Variations
DNA Replication
DNA, Mitochondrial
Gene Expression Regulation, Neoplastic
Glial Fibrillary Acidic Protein
Neural Stem Cells
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
mitochondrial DNA (mtDNA)
glioblastoma multiforme (GBM)
mtDNA copy number
mtDNA set point
Summary As stem cells undergo differentiation, mitochondrial DNA (mtDNA) copy number is strictly regulated in order that specialized cells can generate appropriate levels of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) to undertake their specific functions. It is not understood whether tumor-initiating cells regulate their mtDNA in a similar manner or whether mtDNA is essential for tumorigenesis. We show that human neural stem cells (hNSCs) increased their mtDNA content during differentiation in a process that was mediated by a synergistic relationship between the nuclear and mitochondrial genomes and results in increased respiratory capacity. Differentiating multipotent glioblastoma cells failed to match the expansion in mtDNA copy number, patterns of gene expression and increased respiratory capacity observed in hNSCs. Partial depletion of glioblastoma cell mtDNA rescued mtDNA replication events and enhanced cell differentiation. However, prolonged depletion resulted in impaired mtDNA replication, reduced proliferation and induced the expression of early developmental and pro-survival markers including POU class 5 homeobox 1 (OCT4) and sonic hedgehog (SHH). The transfer of glioblastoma cells depleted to varying degrees of their mtDNA content into immunocompromised mice resulted in tumors requiring significantly longer to form compared with non-depleted cells. The number of tumors formed and the time to tumor formation was relative to the degree of mtDNA depletion. The tumors derived from mtDNA depleted glioblastoma cells recovered their mtDNA copy number as part of the tumor formation process. These outcomes demonstrate the importance of mtDNA to the initiation and maintenance of tumorigenesis in glioblastoma multiforme.
Language eng
DOI 10.1038/cdd.2013.115
Field of Research 06 Biological Sciences
11 Medical And Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2013, Macmillan Publishers Limited
Free to Read? Yes
Use Rights Creative Commons Attribution licence
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