Mitochondrial DNA replication: what we know.

Since the isolation and physical characterization of mammalian mitochondrial DNA (mtDNA) over 35 years ago, numerous works have been published that have examined its physical structure and properties, including its mode of replication and transcription. The established replication model posits that leading-strand replication of mammalian mtDNA begins at closely spaced, defined sites located downstream from a major transcription promoter and proceeds unidirectionally with displacement of the parental leading strand until approximately two-thirds of the closed circular mtDNA has been copied. As a consequence, the replication fork passes a major origin for lagging-strand synthesis, exposing it in single-stranded form. Displacement as a single-strand is thought to allow the characteristic secondary structure of this origin to occur, thereby permitting initiation of lagging-strand synthesis. A natural consequence of the separate and distinct locations of the two origins is that the two segregated progeny mtDNA circles are of two types: one a duplex circle with a newly synthesized leading strand and the other a gapped circle with a partial newly synthesized lagging strand. In each case, the final steps of synthesis and ligation result in closed circular mtDNA products. Recently, mammalian mtDNA isolates have been subjected to 2D-gel electrophoretic analysis in attempts to assign features to mtDNA molecules that, by virtue of their anomalous migration behavior, could infer them to be candidates for replication intermediates. This review will describe the essential features of the historical findings of mammalian mtDNA replication studies and integrate the more recent observations in developing a current model for this process.