Number matters: control of mammalian mitochondrial DNA copy number

Abstract

Regulation of mitochondrial biogenesis is essential for proper cellular functioning. Mitochondrial DNA (mtDNA) depletion and the resulting mitochondrial malfunction have been implicated in cancer, neurodegeneration, diabetes, aging, and many other human diseases. Although it is known that the dynamics of the mammalian mitochondrial genome are not linked with that of the nuclear genome, very little is known about the mechanism of mtDNA propagation. Nevertheless, our understanding of the mode of mtDNA replication has advanced in recent years, though not without some controversies. This review summarizes our current knowledge of mtDNA copy number control in mammalian cells, while focusing on both mtDNA replication and turnover. Although mtDNA copy number is seemingly in excess, we reason that mtDNA copy number control is an important aspect of mitochondrial genetics and biogenesis and is essential for normal cellular function.

Regulation of mitochondrial DNA accumulation during oocyte growth and meiotic maturation in the mouse

“…Our results show that the process of mtDNA accumulation is developmentally regulated in oocytes, but it is not yet clear whether the amount that accumulates is tightly regulated. In somatic cells, either too little or too much mtDNA can be harmful to cell health (Clay Montier et al 2009, Ylikallio et al 2010. In mammalian oocytes, comparing data obtained from different species indicates that, although the amount of mtDNA (and the number of mitochondria) seems to roughly correspond to the size of the oocyte, within a species there is considerable variability among individual oocytes (Piko & Taylor 1987, Kameyama et al 2007, May-Panloup et al 2007, Shoubridge & Wai 2007).…”

“…Several key factors are thought to drive replication (Kanki et al 2004, Pohjoismaki et al 2006, Kang et al 2007, Clay Montier et al 2009, St John et al 2010, Ylikallio et al 2010, including transcription factor associated with mitochondria (TFAM), a high-mobilitygroup; HMG-type protein that coats the mtDNA in a manner possibly analogous to the histones and nuclear DNA; DNA polymerase-g, consisting of a catalytic (POLG (POLGA)) and accessory subunit (POLG2 (POLGB)), that catalyzes synthesis of new mtDNA; nuclear respiratory factor 1 (NRF1); Twinkle, a helicase that has been proposed to be a 'licensing factor;' and mitochondrial single-stranded DNA-binding (mtSSB) protein. Although it seems likely that mtDNA replication in oocytes is similarly controlled, this has not been examined.…”

Correlation between increased copy number of mitochondrial DNA and clinicopathological stage in colorectal cancer

“…Unlike nuclear DNA, mtDNA is present at a consistently high level in each cell, usually 103-104 copies (13). Within various cells, tissues and organs, the copy numbers of mtDNA are different, and this difference can also occur in a given type of cell under different conditions or internal or external microenvironments, …”

An Analogue of Resveratrol HS-1793 Exhibits Anticancer Activity Against MCF-7 Cells Via Inhibition of Mitochondrial Biogenesis Gene Expression

“…Quantitative PCR for mitochondrial DNA To evaluate the effects of HS-1793 or resveratrol on mitochondrial biogenesis, we tested mitochondrial DNA content ratios (Clay Montier et al, 2009). Total DNA including chromosomal DNA and mitochondrial DNA was extracted from HS-1793-or resveratrol-treated cells using the Gentra Puregene kit (QIAGEN) following the manufacturer's instructions.…”