Scientists at the University of California, San Diego have discovered the gene responsible for a cell’s adaptation to oxidative stress. Their findings, published in PLoS Genetics on May 29, could help explain why oxidative stress has been linked to aging and some diseases but in small amounts, offers protection from acute doses.
The researchers used yeast to identify pathways involved in the cell's adaption to hydrogen peroxide, which contributes to oxidative stress. Adaption, or hormesis, is an effect where a toxic substance acts like a stimulant in small doses but is an inhibitor in large doses. Adaptation was elicited by pretreating cells with a mild dose of hydrogen peroxide, followed by a high dose.
They observed that the cells undergoing this adaptation protocol exhibited a smaller reduction in viability than cells exposed to only an acute treatment protocol in which about half of the cells died.
To figure out which genes might control this adaptation mechanism, they report running a series of experiments in which cells were forced to adapt while each gene in the genome was removed, one by one covering a total of nearly 5,000 genes. The team identified Mga2 as a transcription factor that is essential for adaptation.
“This was a surprise, because Mga2 is found at the control point of a completely different pathway than those which respond to acute exposure of oxidative agents,” says Trey Ideker, Ph.D., chief of the division of genetics in the department of medicine at UC San Diego's School of Medicine and professor of bioengineering at the Jacobs School of Engineering. “This second pathway is only active at lower doses of oxidation.”
This finding may explain recent studies suggesting that eating less may raise ROS levels and in doing so, provide protection from acute doses of oxidants, the scientists remark. This is counter to the hypothesis that caloric restriction extends lifespan in some species, because it reduces ROS produced as a by-product of the energy regenerated by mitochondria.
“It may be that adaption to oxidative stress is the main factor responsible for the lifespan-expanding effects of caloric restriction,” according to Dr. Ideker. “Our next step is to figure out how Mga2 works to create a separate pathway to discover the upstream mechanism that senses low doses of oxidation and triggers a protective mechanism downstream.”
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