New research with mice supports the much-debated theory that aging results from the accumulation of assorted blunders in the mitochondrial genome. Because this type of slip-up commonly occurs in mammals, the results could hold significance for humans.
Cells routinely sustain assaults from reactive oxygen species (ROS), which mitochondria produce as they convert food to fuel. The DNA that's ensconced in the nucleus is less vulnerable to this damage. But mitochondrial genomes, located inside these cellular power plants, bear the brunt of the ROS attack. Furthermore, unlike the nucleus, which boasts an arsenal of DNA-proofreading proteins, mitochondria direct scant resources toward error-checking; the burden falls on a single protein, DNA polymerase-g. For these reasons, presumably, glitches accrue in mitochondrial DNA faster than in nuclear DNA.
Because each cell contains hundreds to thousands of mitochondria, many scientists had assumed that a mutation would cause trouble only if mitochondria containing it greatly outnumbered those that didn't. Such events occur: In single cells from older people, the same mutation sometimes appears in most mitochondria. And other studies have shown that a single widespread mutation in mitochondrial DNA can cause cells to atrophy. But some researchers wondered whether the accumulation of multiple random mutations could also wreak havoc for cells.
Aleksandra Trifunovic of the Karolinska Institute in Sweden and colleagues addressed the issue by genetically engineering a mouse that stockpiles mitochondrial DNA mutations indiscriminately. To accelerate the buildup of these mistakes, the team replaced the DNA polymerase-g gene with one that encodes a variant that proofreads poorly. Genetically altered mice accumulated more missing or altered snippets of DNA, evenly distributed across a sample gene. The mutant mice died sooner, on average, and prematurely developed a host of aging-related conditions such as weight loss, osteoporosis, anemia, reduced fertility, and compromised mitochondrial function in the heart, the team reports in the 27 May issue of Nature.
"They're really pinning down a cause of aging," says Matthew Longley, a biochemist at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. This experiment provides the best evidence to date that the accumulation of random mitochondrial DNA mutations induces aging-related dysfunction, he says.
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