Sci. Aging Knowl. Environ., 10 September 2003
Vol. 2003, Issue 36, p. nw126
[DOI: 10.1126/sageke.2003.36.nw126]

NOTEWORTHY ARTICLES

Rusty Hatches

Jammed mitochondrial portals in old cells lock out DNA fix-it protein

Mary Beckman

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/36/nw126

Key Words: 8-oxoguanine • replicative senescence

Doors on old houses tend to stick shut. Similarly, entryways into the energy-producing factories of older cells seize up, according to new research. The jam prevents at least one molecular mechanic from getting inside to fix DNA damage, allowing faults to accumulate with age.

The DNA in cellular power plants called mitochondria suffers constant attack by metabolic byproducts known as reactive oxygen species (ROS). Many scientists think that molecular mayhem from the ROS onslaught underlies aging (see "The Two Faces of Oxygen"). In particular, ROS convert the DNA "letter" guanine (G) to the undesirable 8-oxo-G. If left unrepaired, 8-oxo-G converts to other letters, causing mutations that can lead to cancer or disease. Previous work showed that amounts of 8-oxo-G rise in the mitochondria of aging rats. A protein called OGG1 normally restores the corrupted G. Paradoxically, quantities of that protein also appear to rise over time.

To probe this conundrum, Szczesny and colleagues examined mouse and human mitochondria. First, they measured the amount of OGG1 in mitochondria from livers of 4-month-old and 20-month-old mice, from newly cultured human cells that grow eagerly, and from human cells that have been cultured for so long that they've stopped dividing. As expected, the researchers found more OGG1 in older cells than in younger ones, whether mouse or human. But they also determined that the excess protein was bulkier--a precursor that usually gets trimmed after it enters mitochondria.

Most proteins, including OGG1, are forged outside of the mitochondria and must traverse two membranes to enter. Because the unprocessed version of OGG1 accumulated, the researchers reasoned that it might never reach the interior. To track the movement of OGG1 into the mitochondrion, they used enzymes that trim less of the protein away the farther it penetrates. The protein got stuck on the outer membrane in the older mouse and human cells, but it sailed through both membranes of the younger ones. Together, the data indicate that aging mitochondria rebuff key molecules, undermining vital activities such as OGG1's DNA repair work.

The work is a "nice contribution toward resolving an old dilemma"--why the amount of DNA damage appears to rise along with amounts of the protein that normally remedies it--says molecular gerontologist Vilhelm Bohr of the National Institute on Aging branch in Baltimore, Maryland. No one's yet looked at how enzyme transport contributes to the quality of mitochondrial DNA repair in aging animals, he says. Furthermore, if mitochondria in old cells fail to admit other proteins, other essential activities could falter as well. Knowing that some hatches rust shut with age, researchers might be able to grease the hinges and keep mitochondria healthy for longer.

--Mary Beckman; suggested by Greg Liszt


September 10, 2003
  1. B. Szczesny, T. K. Hazra, J. Papaconstantinou, S. Mitra, I. Boldogh, Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases. Proc. Natl. Acad. Sci. U.S.A., 5 September 2003 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: M. Beckman, Rusty Hatches. Sci. SAGE KE 2003 (36), nw126 (2003).








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