The regulation of mitochondrial DNA copy number in glioblastoma cells

Adam Dickinson, Vanessa K Y Yeung, Jacqueline Faye Donoghue, M J Baker, Richard David William Kelly, Matthew McKenzie, Terrance Grant Johns, Justin Charles St John

Research output: Contribution to journalArticleResearchpeer-review

61 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1644 - 1653
Number of pages10
JournalCell Death and Differentiation
Volume20
Issue number12
DOIs
Publication statusPublished - 2013

Cite this

Dickinson, Adam ; Yeung, Vanessa K Y ; Donoghue, Jacqueline Faye ; Baker, M J ; Kelly, Richard David William ; McKenzie, Matthew ; Johns, Terrance Grant ; St John, Justin Charles. / The regulation of mitochondrial DNA copy number in glioblastoma cells. In: Cell Death and Differentiation. 2013 ; Vol. 20, No. 12. pp. 1644 - 1653.
@article{5a97cade0fda4d5f83518ba16426086e,
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.",
author = "Adam Dickinson and Yeung, {Vanessa K Y} and Donoghue, {Jacqueline Faye} and Baker, {M J} and Kelly, {Richard David William} and Matthew McKenzie and Johns, {Terrance Grant} and {St John}, {Justin Charles}",
year = "2013",
doi = "10.1038/cdd.2013.115",
language = "English",
volume = "20",
pages = "1644 -- 1653",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Nature Publishing Group",
number = "12",

}

The regulation of mitochondrial DNA copy number in glioblastoma cells. / Dickinson, Adam; Yeung, Vanessa K Y; Donoghue, Jacqueline Faye; Baker, M J; Kelly, Richard David William; McKenzie, Matthew; Johns, Terrance Grant; St John, Justin Charles.

In: Cell Death and Differentiation, Vol. 20, No. 12, 2013, p. 1644 - 1653.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The regulation of mitochondrial DNA copy number in glioblastoma cells

AU - Dickinson, Adam

AU - Yeung, Vanessa K Y

AU - Donoghue, Jacqueline Faye

AU - Baker, M J

AU - Kelly, Richard David William

AU - McKenzie, Matthew

AU - Johns, Terrance Grant

AU - St John, Justin Charles

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.nature.com/cdd/journal/v20/n12/pdf/cdd2013115a.pdf

U2 - 10.1038/cdd.2013.115

DO - 10.1038/cdd.2013.115

M3 - Article

VL - 20

SP - 1644

EP - 1653

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

IS - 12

ER -