Discovery of genetic switch critical for cell survival in Hypoxia

Researchers at the University of California, San Diego School of Medicine have identified a critical metabolic "switch" in fruit flies that helps oxygen-deprived cells survive. "A transcriptional suppressor, called hairy, is crucial for reducing the mismatch between supply and demand of oxygen," said Dan Zhou, first author on the study, published October 17 in the open-access journal PLoS Genetics.

Hypoxia-induced injury occurs in the case of heart attack, stroke or other neurological or respiratory conditions which diminish the supply of oxygen to vital tissues and organs. Scientists know that most life forms are able somehow to suppress non-essential activity in order to survive oxygen deprivation, but they didn't know why or how this metabolic slowdown occurs.

Because cellular mechanisms in fruit flies are very similar to those in human cells, the research team developed and studied a strain of fly that developed a tolerance to severe hypoxic conditions through adaptive changes over many generations. In looking at more than 13,000 or about 90 percent of the known genes in the genome of the fruit fly, the researchers were able to examine the difference in gene expression profiles between the hypoxia-tolerant and normal Drosophila melanogaster.

"We discovered that the hairy gene binds to and shuts off, or suppresses, activation of many genes," said principal investigator Gabriel G. Haddad. "When hairy is activated, it puts the brakes on various signaling pathways in the cell, enabling the cells to become resistant to the low-oxygen environment." The hairy switch appears to put into motion a sort of "brown out" in the cells, allowing them to conserve power for critical functions. "While there are multiple pathways that contribute to the ability of this strain of flies to tolerate hypoxia, our study demonstrates that hairy-mediated metabolic suppression plays a critical role," said Haddad.

The researchers hope that by better understanding how the Drosophila cells have developed a strategy for survival under the stress of hypoxia, they may be able to help human cells and tissues adapt and survive under low oxygen situations caused by disease.

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