mckenzie-regulationofmitochondrial-2013.pdf (3.07 MB)
Download fileThe regulation of mitochondrial DNA copy number in glioblastoma cells
journal contribution
posted on 2013-12-01, 00:00 authored by A Dickinson, K Y Yeung, J Donoghue, M J Baker, R Dw Kelly, Matthew McKenzieMatthew McKenzie, T G Johns, J C St JohnAs 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.
History
Journal
Cell death & differentiationVolume
20Issue
12Pagination
1644 - 1653Publisher
Nature Publishing GroupLocation
London, Eng.Publisher DOI
Link to full text
ISSN
1350-9047eISSN
1476-5403Language
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2013, Macmillan Publishers LimitedUsage metrics
Categories
Keywords
AnimalsBiomarkers, TumorBrain NeoplasmsCell DifferentiationCell Line, TumorCell NucleusCell RespirationDNA Copy Number VariationsDNA ReplicationDNA, MitochondrialGene Expression Regulation, NeoplasticGlial Fibrillary Acidic ProteinGlioblastomaHumansMiceNeural Stem CellsUp-RegulationScience & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyCell Biologymitochondrial DNA (mtDNA)glioblastoma multiforme (GBM)tumorigenesismtDNA copy numbermtDNA set pointATPSTEM-CELLSEXPRESSIONASTROCYTOMASNUCLEARCANCERPROLIFERATIONDEPLETIONSEQUENCE