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Mitochondrial DNA mutations in disease and aging.

Park CB, Larsson NG - J. Cell Biol. (2011)

Bottom Line: The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation.There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level.In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Medical Sciences, Ajou University School of Medicine, Suwon 443-721, Korea.

ABSTRACT
The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation. Mutations of mtDNA cause a variety of human mitochondrial diseases and are also heavily implicated in age-associated disease and aging. There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level. In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.

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Different levels at which purifying selection can occur in the maternal germline. (top) Genomes with mutations could be blocked from replication or selectively destroyed without the need for gene expression. (middle) A fragmented mitochondrial network would allow functional testing of individual mtDNA molecules. The presence of a mutated mtDNA molecule would result in a mitochondrion with deficient respiratory chain function, which, in turn, would lead to selection against and/or destruction of this mitochondrion. (bottom) Cells with high levels of mutated mtDNA may fail to compete with respiratory chain–competent cells and may be selected against or undergo apoptosis. The colors indicate mutant (red) and wild-type (blue) mtDNA (top); respiratory chain–deficient (red) and normal (blue) mitochondria (middle); and respiratory chain–deficient (red) and normal (blue) cells (bottom).
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fig3: Different levels at which purifying selection can occur in the maternal germline. (top) Genomes with mutations could be blocked from replication or selectively destroyed without the need for gene expression. (middle) A fragmented mitochondrial network would allow functional testing of individual mtDNA molecules. The presence of a mutated mtDNA molecule would result in a mitochondrion with deficient respiratory chain function, which, in turn, would lead to selection against and/or destruction of this mitochondrion. (bottom) Cells with high levels of mutated mtDNA may fail to compete with respiratory chain–competent cells and may be selected against or undergo apoptosis. The colors indicate mutant (red) and wild-type (blue) mtDNA (top); respiratory chain–deficient (red) and normal (blue) mitochondria (middle); and respiratory chain–deficient (red) and normal (blue) cells (bottom).

Mentions: The transmission of mtDNA mutations through the mouse maternal germline is not neutral, but there is rather a strong purifying selection against deleterious mtDNA mutations (Fan et al., 2008; Stewart et al., 2008b). The mtDNA mutator mouse expresses a catalytic subunit of Pol-γ with deficient proofreading capacity (Table I), which leads to accumulation of high levels of acquired point mutations in mtDNA (Trifunovic et al., 2004). Maternal transmission of this apparently random set of point mutations generated in the mtDNA mutator mouse (Trifunovic et al., 2004) shows a strong selection against amino acid replacement mutations, whereas mutations affecting tRNA or rRNA coding genes are better tolerated (Stewart et al., 2008a,b). Surprisingly, the spectrum of mutations present in offspring to the mtDNA mutator mouse has clear similarities to the naturally occurring spectrum of mutations observed in human populations (Stewart et al., 2008a,b). These results suggest that the naturally occurring spectrum of mtDNA mutations in humans can be explained by mtDNA replication errors that have been subjected to purifying selection in the maternal germline. The molecular mechanism of purifying selection is not understood. Formally, such a selection could occur at different levels (Fig. 3). A mechanism for selection at the level of the mtDNA is not easy to envision, as it involves blocking replication or destroying mutant mtDNA genomes without the need for testing the function of the gene products encoded by the mutant genome. A more plausible mechanism is functional testing of mtDNA at the level of a single organelle (Shoubridge and Wai, 2008). Such a mechanism could involve fragmentation of the mitochondrial network during some stage of oocyte development to permit expression of individual mtDNA molecules and subsequent functional readout of respiratory chain function in single mitochondria (Stewart et al., 2008a). It is also possible that there is a competition between cells during germ cell development and that cells with high levels of mutated mtDNA will be disfavored or undergo apoptosis. Mutations of tRNA or rRNA genes are more likely than amino acid substitutions to escape the purifying selection in the mouse maternal germline, which is consistent with the observation that the majority of pathogenic mutations of human mtDNA affects tRNA genes, although they only occupy ∼9% of the genome (Stewart et al., 2008a). The bottleneck mechanism may be linked to the purifying selection, but it could also represent an independent protective mechanism. It is, of course, possible that a down-regulation of mtDNA copy number and fragmentation of the mitochondrial network may facilitate purifying selection in the maternal germline. However, the bottleneck mechanism could also prevent the spread of low levels of deleterious mtDNA mutations in maternal lineages (Stewart et al., 2008a). Available data on the nature of the bottleneck are mainly correlative, and it will be important to experimentally investigate possible mechanisms, e.g., by introducing pathogenic mtDNA mutations into mice concomitant with experimental manipulation of mtDNA copy number and mitochondrial dynamics in the female germline.


Mitochondrial DNA mutations in disease and aging.

Park CB, Larsson NG - J. Cell Biol. (2011)

Different levels at which purifying selection can occur in the maternal germline. (top) Genomes with mutations could be blocked from replication or selectively destroyed without the need for gene expression. (middle) A fragmented mitochondrial network would allow functional testing of individual mtDNA molecules. The presence of a mutated mtDNA molecule would result in a mitochondrion with deficient respiratory chain function, which, in turn, would lead to selection against and/or destruction of this mitochondrion. (bottom) Cells with high levels of mutated mtDNA may fail to compete with respiratory chain–competent cells and may be selected against or undergo apoptosis. The colors indicate mutant (red) and wild-type (blue) mtDNA (top); respiratory chain–deficient (red) and normal (blue) mitochondria (middle); and respiratory chain–deficient (red) and normal (blue) cells (bottom).
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3105550&req=5

fig3: Different levels at which purifying selection can occur in the maternal germline. (top) Genomes with mutations could be blocked from replication or selectively destroyed without the need for gene expression. (middle) A fragmented mitochondrial network would allow functional testing of individual mtDNA molecules. The presence of a mutated mtDNA molecule would result in a mitochondrion with deficient respiratory chain function, which, in turn, would lead to selection against and/or destruction of this mitochondrion. (bottom) Cells with high levels of mutated mtDNA may fail to compete with respiratory chain–competent cells and may be selected against or undergo apoptosis. The colors indicate mutant (red) and wild-type (blue) mtDNA (top); respiratory chain–deficient (red) and normal (blue) mitochondria (middle); and respiratory chain–deficient (red) and normal (blue) cells (bottom).
Mentions: The transmission of mtDNA mutations through the mouse maternal germline is not neutral, but there is rather a strong purifying selection against deleterious mtDNA mutations (Fan et al., 2008; Stewart et al., 2008b). The mtDNA mutator mouse expresses a catalytic subunit of Pol-γ with deficient proofreading capacity (Table I), which leads to accumulation of high levels of acquired point mutations in mtDNA (Trifunovic et al., 2004). Maternal transmission of this apparently random set of point mutations generated in the mtDNA mutator mouse (Trifunovic et al., 2004) shows a strong selection against amino acid replacement mutations, whereas mutations affecting tRNA or rRNA coding genes are better tolerated (Stewart et al., 2008a,b). Surprisingly, the spectrum of mutations present in offspring to the mtDNA mutator mouse has clear similarities to the naturally occurring spectrum of mutations observed in human populations (Stewart et al., 2008a,b). These results suggest that the naturally occurring spectrum of mtDNA mutations in humans can be explained by mtDNA replication errors that have been subjected to purifying selection in the maternal germline. The molecular mechanism of purifying selection is not understood. Formally, such a selection could occur at different levels (Fig. 3). A mechanism for selection at the level of the mtDNA is not easy to envision, as it involves blocking replication or destroying mutant mtDNA genomes without the need for testing the function of the gene products encoded by the mutant genome. A more plausible mechanism is functional testing of mtDNA at the level of a single organelle (Shoubridge and Wai, 2008). Such a mechanism could involve fragmentation of the mitochondrial network during some stage of oocyte development to permit expression of individual mtDNA molecules and subsequent functional readout of respiratory chain function in single mitochondria (Stewart et al., 2008a). It is also possible that there is a competition between cells during germ cell development and that cells with high levels of mutated mtDNA will be disfavored or undergo apoptosis. Mutations of tRNA or rRNA genes are more likely than amino acid substitutions to escape the purifying selection in the mouse maternal germline, which is consistent with the observation that the majority of pathogenic mutations of human mtDNA affects tRNA genes, although they only occupy ∼9% of the genome (Stewart et al., 2008a). The bottleneck mechanism may be linked to the purifying selection, but it could also represent an independent protective mechanism. It is, of course, possible that a down-regulation of mtDNA copy number and fragmentation of the mitochondrial network may facilitate purifying selection in the maternal germline. However, the bottleneck mechanism could also prevent the spread of low levels of deleterious mtDNA mutations in maternal lineages (Stewart et al., 2008a). Available data on the nature of the bottleneck are mainly correlative, and it will be important to experimentally investigate possible mechanisms, e.g., by introducing pathogenic mtDNA mutations into mice concomitant with experimental manipulation of mtDNA copy number and mitochondrial dynamics in the female germline.

Bottom Line: The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation.There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level.In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Medical Sciences, Ajou University School of Medicine, Suwon 443-721, Korea.

ABSTRACT
The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation. Mutations of mtDNA cause a variety of human mitochondrial diseases and are also heavily implicated in age-associated disease and aging. There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level. In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.

Show MeSH
Related in: MedlinePlus