The Library
The identification of mitochondrial DNA variants in glioblastoma multiforme
Tools
Tools
Tools
Yeung, Ka Yu, Dickinson, Adam, Donoghue, J. F., Polekhina, G., White, S. J., Grammatopoulos, Dimitris K., McKenzie, Matthew, Johnson, T. J. and St John, J. C. (2014) The identification of mitochondrial DNA variants in glioblastoma multiforme. Acta Neuropathologica Communications, 2 (1). 1. doi:10.1186/2051-5960-2-1 ISSN 2051-5960 .
|
PDF
WRAP-identification-mitochondrial-DNA-variants-glioblastoma-multiforme-Yeung-2013.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 2.0.. Download (1904Kb) | Preview |
Official URL: http://dx.doi.org/10.1186/2051-5960-2-1
Abstract
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.
| Item Type: | Journal Article | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine |
||||||||||||||||||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
||||||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Mitochondrial DNA, Nucleotide sequence, Glioblastoma multiforme, Glioblastoma multiforme -- Treatment, Tumors -- Genetic aspects | ||||||||||||||||||||||||
| Journal or Publication Title: | Acta Neuropathologica Communications | ||||||||||||||||||||||||
| Publisher: | BioMed Central Ltd. | ||||||||||||||||||||||||
| ISSN: | 2051-5960 | ||||||||||||||||||||||||
| Official Date: | 2 January 2014 | ||||||||||||||||||||||||
| Dates: |
|
||||||||||||||||||||||||
| Volume: | 2 | ||||||||||||||||||||||||
| Number: | 1 | ||||||||||||||||||||||||
| Article Number: | 1 | ||||||||||||||||||||||||
| DOI: | 10.1186/2051-5960-2-1 | ||||||||||||||||||||||||
| Status: | Peer Reviewed | ||||||||||||||||||||||||
| Publication Status: | Published | ||||||||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||||||||
| Date of first compliant deposit: | 24 January 2020 | ||||||||||||||||||||||||
| Date of first compliant Open Access: | 24 January 2020 | ||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
|
||||||||||||||||||||||||
| Adapted As: |
Request changes or add full text files to a record
Repository staff actions (login required)
 |
View Item |
Downloads
Downloads per month over past year
