Defects of mitochondrial DNA replication

Abstract

Mitochondrial DNA is replicated by DNA polymerase γ in concert with accessory proteins such as the mitochondrial DNA helicase, single-stranded DNA binding protein, topoisomerase, and initiating factors. Defects in mitochondrial DNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mitochondrial DNA deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mitochondrial DNA depletion syndromes such as Alpers or early infantile hepatocerebral syndromes, and mitochondrial DNA deletion disorders, such as progressive external ophthalmoplegia, ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy. This review focuses on our current knowledge of genetic defects of mitochondrial DNA replication (POLG, POLG2, C10orf2, and MGME1) that cause instability of mitochondrial DNA and mitochondrial disease.

Keywords: Alpers syndrome; DNA polymerase γ; POLG; ataxia-neuropathy; mitochondrial DNA depletion syndrome; mitochondrial DNA replication; progressive external ophthalmoplegia.

Conflict of interest statement

Declaration of Conflicting Interests

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

© The Author(s) 2014.

Figures

Figure 1

Schematic diagram of the human DNA polymerase γ gene and protein illustrating the positions of disease mutations.

Figure 2

Three-dimensional structure of the human DNA polymerase γ holoenzyme. The color scheme of the catalytic subunit is: light blue for the polymerase domain, dark blue for the exonuclease region, red for the accessory interacting domain, and orange for the intrinsic processivity domain. The 2 accessory subunits are colored in green for the proximal subunit and grey for the distal subunit. Common disease mutations and the active site residues in the polymerase and exonuclease are colored red and labeled accordingly.