Figure 8.

Strand-asynchronous mtDNA replication is a transcript-dependent mechanism. The usually predominant strand-asynchronous mechanism of mtDNA replication initiating at Ori-H (A), can be repressed and replaced by one that is bidirectional and initiates across a broad zone (Ori-z) (B) (Figures 2–6). Because the relative amount of A and B correlates with the level of mitochondrial transcripts (Figures 2,7), we infer that transcripts are essential for (or impose) the strand-asynchronous mechanism, and that when transcripts are scarce replication reverts to the ancestral type that is synonymous with that found in the nucleus and in prokaryotes. Although replication stalling also produces replication intermediates that are duplex DNA on all branches (e.g. Figures 2 and Supplementary Figure S2), this does not involve any change in the origin of replication (Figures 2C–E and Supplementary Figure S3B), and is instead attributable to early maturation of the lagging strand RNAs (as illustrated in Supplementary Figure S8).