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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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Mitotic segregation of mtDNA. A single mutational event creates heteroplasmy in a cell, but the level of mutated mtDNA (red dots) is very low in comparison with normal mtDNA (green dots). There is no synchronization between cell division and mtDNA replication, and a particular mtDNA molecule may be replicated many times or not at all during a single cell cycle. Repeated cell division will lead to mitotic segregation of normal and mutated mtDNA, and accumulation of mutated mtDNA above a certain threshold level will lead to impaired respiratory chain function.
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fig2: Mitotic segregation of mtDNA. A single mutational event creates heteroplasmy in a cell, but the level of mutated mtDNA (red dots) is very low in comparison with normal mtDNA (green dots). There is no synchronization between cell division and mtDNA replication, and a particular mtDNA molecule may be replicated many times or not at all during a single cell cycle. Repeated cell division will lead to mitotic segregation of normal and mutated mtDNA, and accumulation of mutated mtDNA above a certain threshold level will lead to impaired respiratory chain function.

Mentions: Replication of mtDNA is not linked to the cell cycle, and a particular mtDNA molecule may be replicated many times or not at all as a cell divides (Bogenhagen and Clayton, 1977). This mode of replication makes it possible for a single mutational event to expand clonally or be lost as the cell divides (Fig. 2). The turnover of mtDNA in differentiated tissues has not been extensively studied, and half-lives of ∼14 d have been reported in the rat brain and other tissues (Menzies and Gold, 1971). Thus, there is likely continuous replication of mtDNA in all tissues, which makes segregation of mtDNA mutations possible also in postmitotic cells. Heteroplasmic mtDNA mutations will only cause respiratory chain dysfunction if present above a certain threshold (Fig. 2), which varies depending on the type of mutation and the type of affected tissue. It is generally assumed that mitotic segregation of pathogenic mtDNA mutations is a largely random process and that high mutation levels may be selected against in rapidly dividing cells. However, there are also reports that seemingly neutral polymorphisms in mtDNA may undergo directional selection in certain tissues (Jenuth et al., 1997; Battersby and Shoubridge, 2001; Jokinen et al., 2010).


Mitochondrial DNA mutations in disease and aging.

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

Mitotic segregation of mtDNA. A single mutational event creates heteroplasmy in a cell, but the level of mutated mtDNA (red dots) is very low in comparison with normal mtDNA (green dots). There is no synchronization between cell division and mtDNA replication, and a particular mtDNA molecule may be replicated many times or not at all during a single cell cycle. Repeated cell division will lead to mitotic segregation of normal and mutated mtDNA, and accumulation of mutated mtDNA above a certain threshold level will lead to impaired respiratory chain function.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig2: Mitotic segregation of mtDNA. A single mutational event creates heteroplasmy in a cell, but the level of mutated mtDNA (red dots) is very low in comparison with normal mtDNA (green dots). There is no synchronization between cell division and mtDNA replication, and a particular mtDNA molecule may be replicated many times or not at all during a single cell cycle. Repeated cell division will lead to mitotic segregation of normal and mutated mtDNA, and accumulation of mutated mtDNA above a certain threshold level will lead to impaired respiratory chain function.
Mentions: Replication of mtDNA is not linked to the cell cycle, and a particular mtDNA molecule may be replicated many times or not at all as a cell divides (Bogenhagen and Clayton, 1977). This mode of replication makes it possible for a single mutational event to expand clonally or be lost as the cell divides (Fig. 2). The turnover of mtDNA in differentiated tissues has not been extensively studied, and half-lives of ∼14 d have been reported in the rat brain and other tissues (Menzies and Gold, 1971). Thus, there is likely continuous replication of mtDNA in all tissues, which makes segregation of mtDNA mutations possible also in postmitotic cells. Heteroplasmic mtDNA mutations will only cause respiratory chain dysfunction if present above a certain threshold (Fig. 2), which varies depending on the type of mutation and the type of affected tissue. It is generally assumed that mitotic segregation of pathogenic mtDNA mutations is a largely random process and that high mutation levels may be selected against in rapidly dividing cells. However, there are also reports that seemingly neutral polymorphisms in mtDNA may undergo directional selection in certain tissues (Jenuth et al., 1997; Battersby and Shoubridge, 2001; Jokinen et al., 2010).

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