Sci. Aging Knowl. Environ., 17 April 2002
Go Forth and Multiply: Mutations in mitochondrial DNA take over (Mitochondria)
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/15/nw52
Key Words: mitochondria reactive oxygen species oxidative damage clonal expansion
Abstract: A few rabble-rousers can undermine a whole country if they patiently bring others to their side. Similarly, minority mitochondrial DNAs can apparently swamp other kinds to dominate a cell, according to new work. Although preliminary, the results bolster the theory that changes to the mitochondrial genome underlie aging.
Mitochondria produce energy for cells, but in the process they churn out toxic molecules called reactive oxygen species (ROS) (see "The Two Faces of Oxygen"). Mitochondria carry their own genome, and, because of its proximity to the source of ROS, mitochondrial DNA is especially vulnerable to attack. Accumulation of mutations from such assaults could underlie aging, scientists have speculated. The theory has a flaw, however: Because each cell contains multiple mitochondria, a normal gene in one mitochondrion could compensate for a mutated gene in another, effectively canceling out the mutation. As a result, buildup of random mutations shouldn't cripple a cell. In contrast, buildup of the same mutation in different mitochondria could cause trouble, and previous work suggests that such events can occur. The same point mutation--a change to a single DNA base--can amass in different mitochondria of cultured human cells.
Nekhaeva and colleagues wondered whether one type of mitochondrial genome could overwhelm other versions in individual cells. They isolated mitochondrial DNA from single cells obtained from 13 human subjects who ranged in age from a few months to more than 100 years, and then they used the polymerase chain reaction to amplify the DNA. The researchers sequenced a portion of the genome and looked for changes in its sequence by comparing it to the average sequence of many cells from the same individual. In single cells from older people, the majority of mitochondrial genomes carried a mutation at the same position, suggesting that one mitochondrion can proliferate until it dominates. Cells from younger people rarely contained such propagated mutations, hinting that the alterations crop up with age rather than being present throughout life.
How this "clonal expansion" of mitochondrial mutations occurs isn't clear, but study author Konstantin Khrapko of Harvard Medical School in Boston offers two possibilities. The random redistribution of mitochondria during cell division could, over many divisions, result in cells dominated by a single version of a mitochondrial genome. Alternatively, a mutation that offers an advantage, such as increasing the number of times the organelle duplicates, could help a mitochondrial genome rise to the top. "But this is just speculation," says Krhapko. "The main point is that these clonal expansions exist."
The study rebuts a criticism of the mitochondrial theory of aging, says biochemist Simon Melov of the Buck Institute for Age Research in Novato, California. "There was a consensus that mitochondrial DNA point mutations weren't relevant to aging" because they didn't accumulate in large numbers, he says. The work doesn't address whether the mutations alter mitochondrial and cellular functions, but "the levels [of mutations] reported here are consistent with those found in human diseases." Melov cautions that the study examined a few individuals and a limited region of the mitochondrial genome. Nevertheless, it hints that point mutations are more subversive than previously thought.
--R. John Davenport
E. Nekhaeva, N. D. Bodyak, Y. Kraytsberg, S. B. McGrath, N. J. Van Orsouw, A. Pluzhnikov, J. Y. Wei, J. Vijg, K. Khrapko, Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues. Proc. Natl. Acad. Sci. U.S.A., 9 April 2002 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: R. J. Davenport, Go Forth and Multiply: Mutations in mitochondrial DNA take over (Mitochondria). Science's SAGE KE (17 April 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/15/nw52
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