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DNA Replication in Human Mitochondria

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Abstract

DNA replication in human mitochondria has been studied for several decades; however, its mechanism still remains unclear. During the last 15 years, many new experimental data on the mitochondrial replication have appeared, although extremely contradictory. Two asynchronous (strand displacement and RITOLS) and one synchronous (strand coupled) replication models have been proposed. In the asynchronous models, replication from the origin in the H-chain starts earlier, so that the replication of the two chains ends at different times. The synchronous model is more traditional and implies two replication forks with leading and lagging strands initiated at the same origin. For each of the three models, both confirming and contradicting experimental data exist. Most likely, there is no single model of mitochondrial replication. It is possible that the unique mitochondrial replication machinery that has originated as a results of endosymbiosis has an unexpected variety of replication strategies to maintain the mitochondrial genome. An unusual combination of enzymes of different origin (phage, bacterial, eukaryotic) and unique features of the mitochondrial genome (existance of heavy and light chains, insertions of ribonucleotides, a variety of origins) can allow replication through different mechanisms. In human mitochondria, asynchronous replication seems to dominate; however, synchronous replication is also possible under certain conditions. In the human heart mitochondria, circular mitochondrial DNA (mtDNA) molecules can rearrange in a network of rapidly replicating linear genomes, thereby suggesting possible existence of a wide range of replication mechanisms in the mitochondria. The review describes the main stages of mtDNA replication and enzymes involved in this process, as well as discusses the prospects of mitochondrial replication studies.

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Abbreviations

CSB:

conserved sequence block

H-chain:

heavy chain

L-chain:

light chain

MGME1:

mitochondrial genome maintenance exonuclease 1

mtDNA:

mitochondrial DNA

NCR:

non-coding region

OH :

heavy chain replication origin

OL :

light chain replication origin

ori b and ori z:

origins b and z

POLRMT:

DNA-directed RNA polymerase (mitochondrial)

RITOLS:

RNA incorporated throughout the lagging strand

SSB:

single-strand binding protein

TAS:

termination-associated sequence

TEFM:

mitochondrial transcription elongation factor

TFAM:

transcription factor A of mitochondria

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Funding

The work was supported by the Russian Foundation for Basic Research (project 18-04-01110).

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  1. Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, 119234, Moscow, Russia

    L. A. Zinovkina

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  1. L. A. Zinovkina
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Correspondence to L. A. Zinovkina.

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Russian Text © The Author(s), 2019, published in Biokhimiya, 2019, Vol. 84, No. 8, pp. 1115–1128.

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Zinovkina, L.A. DNA Replication in Human Mitochondria. Biochemistry Moscow 84, 884–895 (2019). https://doi.org/10.1134/S0006297919080042

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  • DOI: https://doi.org/10.1134/S0006297919080042

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