Sci. Aging Knowl. Environ., 26 May 2004
Symphony of Errors
Sloppy proofreading of mitochondrial DNA spurs a premature demise
An orchestra's sound quality suffers whether each member of the cello section flubs a particular pitch or scattered violinists play random notes offkey. Similarly, cells can atrophy when they amass many identical mitochondrial DNA defects or, according to new work, multiple haphazard flaws. The findings support the much-debated theory that accumulation of assorted blunders in the mitochondrial genome underlies aging. 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 (see "The Two Faces of Oxygen"). Because of their location, mitochondrial genomes, separate from the bulk of DNA in the cell's nucleus, 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-. For these reasons, presumably, glitches accrue in mitochondrial DNA faster than in nuclear DNA. Some researchers had proposed that they hasten an organism's decline, but they might instead just build up over time. Because each cell contains hundreds to thousands of mitochondria, many scientists had assumed that mutations in individual mitochondria wouldn't cause trouble because other mitochondria in the same cell could pick up the slack; a defect would hurt 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, suggesting that one flawed mitochondrial genome can eventually swamp others (see "Go Forth and Multiply"). But some researchers wondered whether the accumulation of multiple random mutations would induce age-related defects.
Trifunovic 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- gene with one that encodes a variant that proofreads poorly. Genetically altered mice copied mitochondrial DNA as efficiently as normal animals did but accumulated more deletions and three- to fivefold more single DNA-base changes, 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.
"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. Jeff Stuart, a mitochondrial bioenergeticist at Brock University in Ontario, Canada, praises the study's design because it enabled the researchers to document mitochondrial failure and aging-associated defects in young mice; most previous experiments had examined the mitochondria of older animals, in which other aging-related conditions might have confounded the observations, Stuart says. A finer understanding of the mechanisms that link mitochondrial DNA damage to aging-related defects could lead to therapeutics that keep us playing a youthful tune.
May 26, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150