title: The regulation of mitochondrial DNA copy number in glioblastoma cells.
abstract: 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.
authors.affiliation: 1] The Mitochondrial Genetics Group, Centre for Genetic Diseases, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia [2] Molecular Basis of Metabolic Disease, Division of Metabolic and Vascular Health, Warwick Medical School, The University of Warwick, Clifford Bridge Road, Coventry, CV2 2DX, UK.
authors.forename: A
authors.initials: A
authors.lastname: Dickinson
authors.forename: K Y
authors.initials: KY
authors.lastname: Yeung
authors.forename: J
authors.initials: J
authors.lastname: Donoghue
authors.forename: M J
authors.initials: MJ
authors.lastname: Baker
authors.forename: R Dw
authors.initials: RD
authors.lastname: Kelly
authors.forename: M
authors.initials: M
authors.lastname: McKenzie
authors.forename: T G
authors.identifier: 0000000288744543
authors.initials: TG
authors.lastname: Johns
authors.forename: J C
authors.initials: JC
authors.lastname: St John
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics; D019069:Cell Respiration / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D004272:DNA, Mitochondrial; D005904:Glial Fibrillary Acidic Protein