Sci. Aging Knowl. Environ., 27 March 2002
Trash Cache: Secret mitochondrial weapon fights oxidative damage (Oxidative damage)
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/12/nw41
Key Words: DNA glycosylase oxidative damage base excision repair mitochondria
Abstract: TAHOE CITY, CALIFORNIA--A good sanitation service keeps trash from swamping the streets. New work presented at the DNA Helicases, Cancer, and Aging Keystone Symposium here identifies the duties of two cellular garbage removers. The work suggests that mouse mitochondria--cellular compartments where molecular offal collects in large amounts--exploit unique machinery to deal with the scourge.
Like any power plant, mitochondria churn out hazardous waste as they convert food into cellular fuel. Some of these compounds--reactive oxygen species (ROS)--cripple DNA, proteins, and membranes and likely contribute to aging (see "The Two Faces of Oxygen"). ROS produce more than 100 varieties of modified DNA bases, each of which carries a distinctive chemical flag. These changes can mutate genes or kill cells by impeding DNA-copying machinery. Organisms use a panoply of enzymes called DNA glycosylases to snip out each type of altered base; other enzymes then fill in the empty space with the proper DNA building block, using the opposite DNA strand as a guide. Although researchers have gathered piles of information about bacterial versions of such enzymes, knowledge about mammalian DNA glycosylases remains sparse.
Lars Eide of the National Hospital of Norway in Oslo and colleagues have now identified the targets of two mouse genes that likely encode DNA glycosylases. The group studied strains of mice that lack either ogg1, nth1, or both. The researchers broke open liver cells from each type of animal. Then they separated nuclei and mitochondria and extracted their contents. To determine how the absence of the genes affects trash disposal in the different cellular compartments, the team measured the ability of each extract to trim particular types of altered DNA bases. Nuclear and mitochondrial extracts from normal mice efficiently snipped 8-oxoguanine, 5-methylcytosine, and formamidopyrimidine. Extracts from mice that lack ogg1 didn't scissor 8-oxoguanine, whereas those from mice without nth1 didn't clip 5-methylcytosine. The results suggest that in the nucleus and mitochondria, ogg1 roots out 8-oxoguanine and nth1 crops 5-methylcytosine. Lack of either gene reduced pruning of formamidopyrimidine in the nuclear extract, suggesting that both help clear this alteration in the nucleus.
Analysis of the double mutants revealed that mitochondria beat the nucleus for grime-fighting power. Nuclear extracts from mice that lack both ogg1 and nth1 couldn't trim any of the three altered bases. But mitochondrial extracts from the same mice surpassed those from either of the single mutants in cutting 8-oxoguanine and formamidopyrimidine. Eide speculates that an as-yet-unidentified glycosylase that dwells only in mitochondria might ramp up to compensate for the absence of the two other enzymes.
The results suggest that mammals harbor garbage-removal mechanisms that are unique to mitochondria, where oxidative damage predominantly occurs. Although the researchers haven't extensively analyzed the mice, they have made one mysterious discovery: Rodents that lack ogg1 enjoy a normal life-span even though they accumulate 8-oxoguanine damage, which likely mutates DNA. Further analysis of the mutant mice will perhaps reveal how animals either orchestrate extra garbage sweeps through especially sullied cellular neighborhoods or persist, despite piles of trash.
--R. John Davenport
Citation: R. J. Davenport, Trash Cache: Secret mitochondrial weapon fights oxidative damage (Oxidative damage). Science's SAGE KE (27 March 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/12/nw41
Science of Aging Knowledge Environment. ISSN 1539-6150