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Review
. 2009 Feb;10(2):137-43.
doi: 10.1038/embor.2008.242. Epub 2009 Jan 16.

Mouse models of mitochondrial DNA defects and their relevance for human disease

Henna Tyynismaa  1 , Anu Suomalainen
Affiliations
Review

Mouse models of mitochondrial DNA defects and their relevance for human disease

Henna Tyynismaa et al. EMBO Rep. 2009 Feb.

Abstract

Qualitative and quantitative changes in mitochondrial DNA (mtDNA) have been shown to be common causes of inherited neurodegenerative and muscular diseases, and have also been implicated in ageing. These diseases can be caused by primary mtDNA mutations, or by defects in nuclear-encoded mtDNA maintenance proteins that cause secondary mtDNA mutagenesis or instability. Furthermore, it has been proposed that mtDNA copy number affects cellular tolerance to environmental stress. However, the mechanisms that regulate mtDNA copy number and the tissue-specific consequences of mtDNA mutations are largely unknown. As post-mitotic tissues differ greatly from proliferating cultured cells in their need for mtDNA maintenance, and as most mitochondrial diseases affect post-mitotic cell types, the mouse is an important model in which to study mtDNA defects. Here, we review recently developed mouse models, and their contribution to our knowledge of mtDNA maintenance and its role in disease.

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Figures

Figure 1
Figure 1
Essential mitochondrial DNA maintenance proteins. All mtDNA maintenance proteins are encoded by nuclear genes, which are transcriptionally regulated by factors such as NRF1. Some proteins are involved directly in mtDNA replication and some provide nucleotides for DNA synthesis. The specific function of some of these proteins is still unclear but their absence induces mtDNA defects. ANT1, adenine nucleotide translocator 1; DGUOK, deoxyguanosine kinase; HSP40, heat-shock protein 40 mitochondrial chaperone; MPV17, mitochondrial inner membrane protein; mtDNA, mitochondrial DNA; NRF1, nuclear respiratory factor 1; OXPHOS, oxidative phosphorylation; p53R2, ribonucleotide reductase subunit; SSBP, single-stranded DNA-binding protein; TFAM, mitochondrial transcription factor A; TK2, thymidine kinase 2; TOPO, topoisomerase; TP, thymidine phosphorylase.
Figure 2
Figure 2
Mouse models of mitochondrial DNA and its maintenance. (A) Main tissue manifestations of mtDNA disease models. (B) Crucial tissue manifestations of mice lacking mtDNA maintenance proteins. Mice in which mtDNA replication proteins are absent die during embryonic development, whereas those without proteins involved in maintaining the nucleotide pools present postnatal symptoms. (C) Various tissue manifestations of prematurely aged Mutator mice. ΔmtDNA, Mito-mice with single mtDNA deletion; ANT1, adenine nucleotide translocator; HSP40, heat-shock protein 40 mitochondrial chaperone; MPV17, mitochondrial inner membrane protein; mtDNA, mitochondrial DNA; NRF1, nuclear respiratory factor 1; p53R2, ribonucleotide reductase subunit; POLG, DNA polymerase γ; PstI, restriction endonuclease; RNaseH, ribonuclease H1; TFAM, mitochondrial transcription factor A; TK2, thymidine kinase 2.
None
Henna Tyynismaa (left) & Anu Suomalainen
See this image and copyright information in PMC

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