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The identification of mitochondrial DNA variants in glioblastoma multiforme

Yeung, Ka Yu, Dickinson, Adam, Donoghue, Jacqueline F., Polekhina, Galina, White, Stefan J., Grammatopoulos, Dimitris K., McKenzie, Matthew, Johns, Terrance G. and St John, Justin C. 2014, The identification of mitochondrial DNA variants in glioblastoma multiforme, Acta neuropathologica communications, vol. 2, no. 1, pp. 1-21, doi: 10.1186/2051-5960-2-1.

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Title The identification of mitochondrial DNA variants in glioblastoma multiforme
Author(s) Yeung, Ka Yu
Dickinson, Adam
Donoghue, Jacqueline F.
Polekhina, Galina
White, Stefan J.
Grammatopoulos, Dimitris K.
McKenzie, MatthewORCID iD for McKenzie, Matthew orcid.org/0000-0001-7508-1800
Johns, Terrance G.
St John, Justin C.
Journal name Acta neuropathologica communications
Volume number 2
Issue number 1
Start page 1
End page 21
Total pages 21
Publisher BioMed Central
Place of publication London, England
Publication date 2014-01-02
ISSN 2051-5960
Keyword(s) Animals
Antimetabolites
Brain
Brain Neoplasms
Cell Line, Tumor
Cell Transformation, Neoplastic
DNA, Mitochondrial
Gene Expression Regulation, Neoplastic
Genetic Variation
Glioblastoma
Glycolysis
Heterografts
High-Throughput Nucleotide Sequencing
Humans
Mice
Mitochondrial Proton-Translocating ATPases
Models, Molecular
Neural Stem Cells
Oxidative Phosphorylation
Zalcitabine
Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
Mitochondrial DNA
Tumorigenesis
Genetic variants
Aerobic glycolysis
Depletion
Summary BACKGROUND: Mitochondrial DNA (mtDNA) encodes key proteins of the electron transfer chain (ETC), which produces ATP through oxidative phosphorylation (OXPHOS) and is essential for cells to perform specialised functions. Tumor-initiating cells use aerobic glycolysis, a combination of glycolysis and low levels of OXPHOS, to promote rapid cell proliferation and tumor growth. Glioblastoma multiforme (GBM) is an aggressively malignant brain tumor and mitochondria have been proposed to play a vital role in GBM tumorigenesis.

RESULTS: Using next generation sequencing and high resolution melt analysis, we identified a large number of mtDNA variants within coding and non-coding regions of GBM cell lines and predicted their disease-causing potential through in silico modeling. The frequency of variants was greatest in the D-loop and origin of light strand replication in non-coding regions. ND6 was the most susceptible coding gene to mutation whilst ND4 had the highest frequency of mutation. Both genes encode subunits of complex I of the ETC. These variants were not detected in unaffected brain samples and many have not been previously reported. Depletion of HSR-GBM1 cells to varying degrees of their mtDNA followed by transplantation into immunedeficient mice resulted in the repopulation of the same variants during tumorigenesis. Likewise, de novo variants identified in other GBM cell lines were also incorporated. Nevertheless, ND4 and ND6 were still the most affected genes. We confirmed the presence of these variants in high grade gliomas.

CONCLUSIONS: These novel variants contribute to GBM by rendering the ETC. partially dysfunctional. This restricts metabolism to anaerobic glycolysis and promotes cell proliferation.
Language eng
DOI 10.1186/2051-5960-2-1
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2014, Yeung et al
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30111624

Document type: Journal Article
Collections: School of Life and Environmental Sciences
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.