Sci. Aging Knowl. Environ., 24 September 2003
Vol. 2003, Issue 38, p. nw132
[DOI: 10.1126/sageke.2003.38.nw132]

NOTEWORTHY ARTICLES

Trouble Starts Within

Mitochondria's poisons destabilize the nuclear genome

R. John Davenport

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/38/nw132

Key Words: mouse embryonic fibroblasts • caspase-3 • MnSOD

Hurricanes can churn frenzied seas that wash away houses, but ordinary waves can nip at a home's integrity too. Whether the same concept applies to the rain of toxic chemicals in cells is unclear. In lab experiments, deluges of oxygen radicals cripple cells and organisms, but no one knows whether the trickle of compounds produced inside cells during everyday life fosters disease. A new study supports that link, however. Cells with weakened oxidant defenses show dramatic alterations in chromosome structure--changes that can spur cancer and perhaps aging.

Mitochondria, the cell's energy-producing machines, generate noxious compounds called reactive oxygen species (ROS), which mar DNA and other molecules. Such oxidative damage might spur disease and aging by impairing cellular activities (see "The Two Faces of Oxygen"). In many experiments, however, researchers subject cells or animals to large amounts of oxidants, leaving doubt about whether the smaller quantities of naturally produced ROS cause trouble. "The question is, are they really that dangerous," says molecular biologist Toren Finkel of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, "or is this much ado about nothing?"

Instead of adding oxidants, researchers trying to ascertain the effect of mitochondrially made ROS have genetically quelled natural defenses against ROS. For example, rodents without the mitochondrial antioxidant enzyme superoxide dismutase (SOD2) perish at birth; rodents with a half-strength dose of SOD2 mature normally but develop unusual types of cancer (see "Is Less Enough?"). That result surprised researchers because they didn't expect increased quantities of ROS in the mitochondria to sully nuclear DNA. Cells from mice without SOD2 accrue chemical marks of oxidative damage on their nuclear DNA, but no one had investigated whether blunting the antioxidant spurs the massive chromosomal changes typical of cancer.

To address the issue, molecular biologist Simon Melov and colleagues at the Buck Institute for Age Research in Novato, California, isolated connective tissue cells from mouse embryos that lack both copies of the sod2 gene. The researchers examined the cells' chromosomes for defects. Chromosomes broke 2.5 times more frequently in cells without SOD2 than in normal cells, and they fused together about three times as often. Furthermore, cells without SOD2 harbored nine times as many chromosomes with large segments of swapped DNA as did normal cells.

Such chromosomal reconstruction can spur cancer and might underlie some premature aging syndromes. By implicating oxidants in dramatic genetic rearrangements, the new work bolsters the idea that mitochondria-produced ROS can spur disease, says Finkel. Chromosomes in human cells are less brittle than those in mouse cells, notes cell biologist Peter Hornsby of the University of Texas Health Science Center in San Antonio (see Hornsby Perspective). He'd like to see researchers block SOD2 in human cells to find out whether their chromosomes are as vulnerable as those of mice. How ROS devastate chromosomes remains unclear. They might drift to the nucleus and sever DNA, says Melov, or they might extinguish fuel production in mitochondria and cripple energy-dependent processes that maintain the genome. Fleshing out such details might reveal strategies for weathering everyday oxidative storms.

--R. John Davenport


September 24, 2003
  1. E. Samper, D. G. Nicholls, S. Melov, Mitochondrial oxidative stress causes chromosomal instability of mouse embryonic fibroblasts. Aging Cell, 11 September 2003 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: R. J. Davenport, Trouble Starts Within. Sci. SAGE KE 2003 (38), nw132 (2003).








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