Sci. Aging Knowl. Environ., 5 November 2003
Stem cells in the gut pile up mutations in mitochondrial DNA
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/44/nw150
Key Words: cytochrome c oxidase succinate dehydrogenase heteroplasmy homoplasmy
Dark crypts swarming with cloned mutants: It's not the premise for a grade B horror film but the result of a new study. The work is the first to reveal that intestinal stem cells amass DNA mutations in their mitochondria, and it raises the possibility that the accumulation of such defects as we age could choke stem cells.
Mitochondria convert food into cellular energy. But in the process, their energy-producing machinery tarnishes itself by spewing reactive oxygen species (ROS), harmful molecules that attack proteins, DNA, and lipids (see "The Two Faces of Oxygen"). Mitochondria carry their own DNA, and some scientists posit that accumulated mutations in mitochondrial DNA--caused in part by ROS--could foster aging by thwarting energy production. Scientists have found that mutations in mitochondrial DNA accrue in cells that no longer divide. Neurologist Douglass Turnbull and gerontologist Tom Kirkwood, both at the University of Newcastle, U.K., teamed up to investigate whether mitochondrial DNA mutations heap up in stem cells, which divide to replenish specialized cells in particular tissues.
Turnbull, Kirkwood, and colleagues dug into colonic crypts, funnels of cells in the lining of the colon. These structures harbor stem cells that divide to make functional colon cells. Because new colon cells loiter in the crypt, researchers can use the structure to track stem cells and their offspring. The team obtained samples of colon tissue from patients aged 35 to 80. The researchers stained the tissue with chemicals that permitted them to gauge the activity of a mitochondrial enzyme--produced from genes in both the mitochondria and the nucleus--important for energy generation. Although most crypts held only normal cells, others contained cells in which the enzyme malfunctioned. Moreover, in some crippled crypts, cells with the enzyme defect formed rows, suggesting that they originated from the same mutated stem cell.
The researchers next sought a genetic cause for the cells' enzymatic deficiency. They sequenced mitochondrial DNA from cells in the crypts and looked for glitches. In many of the crypts with enzymatic deficiencies, cells carried mutations in the genes that encode the enzyme. The team also found that the number of defective crypts increased with age. "It was a complete surprise that we saw any defective crypts," says Turnbull. "We thought that if you had a deleterious mitochondrial mutation, stem cells would stop dividing." Whether the mutations handicap cells isn't clear yet.
It's the first time anyone has documented mitochondrial DNA mutations in stem cells, says geneticist Guiseppe Attardi of the California Institute of Technology in Pasadena. He'd like to see whether the same phenomenon occurs in other types of stem cells--muscle, for instance. Additional experiments with the colonic crypts should clarify whether the mitochondrial DNA mutations--and not nuclear ones--impair cell function, says Attardi. How much the phenomenon contributes to aging is an unanswered question. "People have tended to think of stem cells as almost immortal," says Kirkwood, but his results support the idea that stem cells are not immune to the actions of aging. Understanding how time exacts its toll on stem cells could help researchers come up with a less scary ending to this tale from the crypts.
--R. John Davenport
November 5, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150