Sci. Aging Knowl. Environ., 6 October 2004
Fanning the Flames
Telomerase aggravates oxidative damage in mitochondria
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/40/nf90
Some children do their chores at home but throw spitballs at school. Similarly, the enzyme telomerase helps cells by tending to the ends of their chromosomes in the nucleus, but it makes mischief elsewhere. A new study reveals that telomerase makes a second home in mitochondria--the cell's powerhouses--where it enhances damage from oxidants. The work identifies a new location for the enzyme, but further studies are necessary to illuminate how it accelerates decay.
Telomeres, protective caps on chromosome tips, recede each time a cell divides, and telomerase stitches on new DNA to keep chromosomes healthy. Without it, cells in culture eventually stop dividing, entering a state known as senescence; those that manufacture telomerase reproduce indefinitely. But cultured cells with telomerase suffer greater than normal damage to the DNA in their mitochondria when exposed to hydrogen peroxide, biochemist Bennett Van Houten of the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, and colleagues previously noted. The observation suggested that telomerase might operate--perhaps with harmful consequences--in cellular compartments other than the nucleus.
To address that idea, the researchers analyzed the sequence of the protein component of telomerase, known as hTERT; they found that it contains a run of amino acids known to send proteins to mitochondria. Next, they joined hTERT to a fluorescent protein and tracked the duo's location in cells. The fluorescent protein lit up mitochondria as well as the nucleus. Then the team isolated the contents of mitochondria from cells that produce telomerase and demonstrated that the extract could extend artificial telomeres in a test tube. Together, the results suggest that mitochondria bear active telomerase.
To investigate whether telomerase fuels oxidative damage, the team doused cells with hydrogen peroxide and assessed how much injury their DNA sustained. The more telomerase a cell produced, the more the chemical marred its mitochondrial DNA and the more likely the cell was to die. However, cells suffered almost no damage to their nuclear DNA in the presence of hydrogen peroxide, regardless of telomerase quantity. Together, the results suggest that telomerase's presence in mitochondria renders cells especially susceptible to oxidative stress. Van Houten says he'd like to verify that idea by obliterating telomerase's ticket to the mitochondria and assessing whether cells fend off peroxide damage more successfully. He doesn't know why telomerase heightens destruction but notes that iron might be involved. Hydrogen peroxide requires iron to form free radicals, the agents that oxidize DNA, and additional studies by his team suggest that iron quantities rise in cells that produce telomerase.
"The importance of this paper is to point out a connection between telomerase and mitochondria," says cellular gerontologist Thomas von Zglinicki of the University of Newcastle, U.K. "The real question [now] is what is telomerase doing there?" The study contradicts the typical view of the enzyme as one that helps cells survive, he says. "But there might be different mechanisms depending on the stress or where [in the cell] you look." Deciphering those mechanisms should reveal the secret behind telomerase's inconsistent behavior.
October 6, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150