Environmental Factor, July 2009, National Institute of Environmental Health Sciences
Findings Show Protection Against Oxidative Stress
By Negin Martin
High levels of reactive oxygen species (ROS) are implicated in cardiovascular and neurodegenerative disease and are proposed to accelerate aging and promote cancer, according to new NIEHS-funded (http://tools.niehs.nih.gov/portfolio/sc/detail.cfm?appl_id=7475178) research published in PLoS Genetics. Led by Trey Ideker, Ph.D., the study identified the components of a remarkable pathway that triggers adaptation and protects cells against acute oxidative stress. The study's findings point to the possibility that manipulating the function of the identified genes has the potential to lower incidence of disease and to prolong life.
Ideker (http://chianti.ucsd.edu/idekerlab/pages/ideker.html) is chief of the Division of Genetics in the Departments of Medicine and Bioengineering at the University of California, San Diego (UCSD) and a member of the Moores UCSD Cancer Center. His innovative use of genomic and bioinformatic approaches has yielded deep insights into molecular pathways and disease.
In the study (http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000488) , Ideker examined the mechanism of adaptation to oxidative stress using yeast as a model organism. His findings demonstrate that pretreatment of yeast with low levels of hydrogen peroxide, as a source of oxidative stress, protects yeast against acute doses of hydrogen peroxide. Low levels of oxidants trigger an adaptive response that is not active during high-dose treatments.
"Our study runs counter to the conventional wisdom that antioxidants are good for you," Ideker said of his findings. "It appears that at least a small amount of oxidant can have beneficial effects."
Genetic screening of 4,831 single-gene deletion strains of yeast revealed that mild/adaptive exposures and acute exposures activate different pathways inside the cell. The adaptive pathway requires the presence of transcriptional regulators such as Yap1, Skn7, Rox1, and especially Mga2 — a previously identified response gene expressed in hypoxia.
Mga2 targets the metabolism of a cholesterol-like compound, ergosterol, that gets incorporated into the plasma membrane and makes it more rigid. Ideker hypothesizes that pretreatment of yeast with hydrogen peroxide potentiates Mga2 and increases ergosterol levels. Increase in membrane rigidity, due to ergosterol incorporation, inhibits the diffusion of H2O2 across the membrane and entry into the cell. Indeed, direct measurement of ergosterol levels shows lower concentrations in mga2 and rox1 deleted strains.
Mga2 also regulates the components of fatty acid pathway that may contribute to changes in the permeability and stability of cellular membranes. Exposure to low doses of ROS — generated by H2O2 in this study — can help cells adapt to the environment by changing the membrane structure and making it more resistant to higher doses of ROS. Ideker plans to test this hypothesis in higher organisms.
Oxidative stress and generation of ROS are important factors in aging. Because of their role, a general assumption has been that by lowering the levels of ROS, one can extend lifespan.
ROS or oxidants are byproducts of normal metabolic processes. The highly reactive nature of oxidants is damaging to cells, and they are therefore promptly converted to less reactive species by specialized enzymes — superoxide dismutases, catalases, and various peroxidases — inside the cell. Organs with high metabolic rate such as brain are especially vulnerable to damage by oxidants. Antioxidants, such as vitamin C, E and glutathione, can help cells lower the levels of oxidants.
Citation: Kelley R, Ideker T. (http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000488) 2009. Genome-wide fitness and expression profiling implicate Mga2 in adaptation to hydrogen peroxide. PLoS Genet 5(5):e1000488. doi:10.1371/journal/pgen.1000488. Epub May 29.
(Negin Martin, Ph.D., is a biologist in the NIEHS Laboratory of Neurobiology Viral Vector Core Facility and a 2009 Science Communication Fellow with Environmental Health Sciences. She recently completed a postdoctoral fellowship with the NIEHS Membrane Signaling Group.)