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First published online 30 October 2007
doi: 10.1242/jcs.016972

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Mitochondrial DNA replication during differentiation of murine embryonic stem cells

Joao M. Facucho-Oliveira^1,*, Jon Alderson¹, Emma C. Spikings¹, Stuart Egginton² and Justin C. St. John^1,*,

¹ The Mitochondrial and Reproductive Genetics Group, The Medical School, The University of Birmingham, Birmingham, B15 2TT, UK
² The Angiogenesis Research Group, The Medical School, The University of Birmingham, Birmingham, B15 2TT, UK

Author for correspondence (e-mail: j.c.st-john{at}warwick.ac.uk)

Accepted 12 September 2007

Oxidative phosphorylation (OXPHOS), the intracellular process that generates the majority of the ATP of a cell through the electron-transfer chain, is highly dependent on proteins encoded by the mitochondrial genome (mtDNA). MtDNA replication is regulated by the nuclear-encoded mitochondrial transcription factor A (TFAM) and the mitochondrial-specific DNA polymerase gamma, which consists of a catalytic (POLG) and an accessory (POLG2) subunit. Differentiation of pluripotent embryonic stem cells (ESCs) into specific cell types requires expansion of discrete populations of mitochondria and mtDNA replication to meet the specific metabolic requirements of the cell. We determined by real-time PCR that expression of pluripotent markers is reduced before the upregulation of Polg, Polg2 and Tfam in spontaneously differentiating R1 murine (m)ESCs, along with transient increases in mtDNA copy number. In D3 mESCs, the initial transient increase did not take place. However, precursors of neuronal and cardiomyocyte differentiation were positive for both POLG and TFAM. Similar-stage ESCs also showed active mtDNA replication, identified by 5-bromo-2'-deoxy-uridine labelling, as mtDNA copy number increased. Retinoic-acid-induced differentiation resulted in more consistent patterns of replication and upregulation of Polg, Polg2 and Tfam, whereas siRNA knockdown demonstrated that steady-state expression of POLG is essential for maintaining pluripotency.

Key words: Mitochondrial DNA, Replication, POLG, TFAM, Embryonic stem cells

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