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.

Fig. 1

Threshold hypothesis of mtDNA copy number control. MtDNA copy number is regulated by thresholds. When the copy number reaches the lower threshold, unknown factors trigger the upregulation of the mtDNA replication machinery that instigates replication to push the mtDNA copy number back up. When the copy number reaches the higher threshold, unknown factors trigger the upregulation of proteins that lead to mtDNA degradation to push the mtDNA copy number back down.