Dickinson 2013 Thesis University of Warwick - Great Britain

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Dickinson A (2013) The role of mitochondrial DNA in tumorigenesis. Thesis University of Warwick - Great Britain 292pp.

» warwick.ac.uk 58415

Dickinson A (2013) Thesis University of Warwick - Great Britain

Abstract: Mitochondria are cytoplasmic organelles that are found in almost all mammalian cells. Mitochondria contain their own genome, mitochondrial DNA (mtDNA) that encodes 13 subunits of the electron transfer chain, which is the primary generator of cellular energy. Precise regulation of mtDNA copy number is essential for normal cell function and also the differentiation of stem cells into specialized cell types. Abnormal regulation of mtDNA copy number is associated with cellular dysfunction, mitochondrial disease and more recently cancer. Glioblastoma multiforme (GBM) is a highly malignant subgroup of brain tumors that exhibit similar characteristics to human neural stem cells (hNSCs) including multipotency and the expression of the stem cell factors. It is unknown how GBM cells regulate their mtDNA copy number during differentiation and whether this differs to hNSCs. Furthermore, it is unknown what role mtDNA plays in the gene expression profiles and the tumorigenicity of GBM. To address these issues, GBM cells and hNSCs were differentiated for 28 days and their mtDNA copy number and gene expression were analyzed. In addition, GBM cells were progressively depleted of their mtDNA using the depletion agent, 2'-3'-dideoxycytidine, and their in vivo tumorigenicity assessed. hNSCs and GBM cell lines regulated their copy number in a differential manner during differentiation. hNSCs progressively expanded their mtDNA copy number and adopted a differentiated phenotype whilst GBM cells failed to mimic these processes and their differentiation was incomplete. In addition, progressive depletion of mtDNA copy number in GBM cells resulted in reduced proliferation rates and the down regulation of stem cell factors. In vivo, mtDNA depleted GBM cells formed tumors at a reduced rate and frequency relative to nondepleted cells. These outcomes demonstrate that mtDNA copy number is abnormally regulated in GBM cells and hinders their ability to complete differentiation. The failure of mtDNA-depleted GBM cells to consistently generate tumors strongly suggests that maintenance of mtDNA copy number is essential for GBM cells to be tumorigenic.

Labels: MiParea: Respiration, mtDNA;mt-genetics  Pathology: Cancer 

Organism: Human  Tissue;cell: Other cell lines  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k