As women age, their stockpile of immature eggs, called oocytes, diminishes through cell death, eventually leading to infertility. In studies with frog oocytes, the Duke researchers found that the nutrient storehouse, or yolk, plays a key role in regulating the survival of these cells. Depleting the nutrients triggers apoptosis – programmed cell death – and adding nutrients prolongs the life of eggs, they found. The study offers potential for developing oocyte-protective therapies for women undergoing chemotherapy, as well as potential targets for improved infertility treatments, the researchers said.
"This discovery provides a basic science underpinning for understanding the mechanisms of oocyte death and a way to identify potential clinical treatments," said Sally Kornbluth, Ph.D., senior study author and an associate professor of pharmacology and cancer biology at Duke University Medical Center.
Adds Leta Nutt, Ph.D., lead author of the study, "Our work provides evidence for a metabolic timer in which oocytes that use up their energy stores are fated to die." Nutt is a postdoctoral researcher in Duke's department of pharmacology and cancer biology.
The results appear in the Oct. 7, 2005, issue of Cell. The work was supported by the National Institutes of Health, the Sidney Kimmel Foundation for Cancer Research, the V Foundation for Cancer Research and the Triangle Community Foundation.
Oocytes are one of the few cells to rely entirely on internal energy stores, receiving no nutrients from the body. Human oocytes have a relatively small nutrient stockpile compared to the frog oocytes studied by the Duke researchers.
To explore the link between energy stores and apoptosis (cell death), the researchers both extended the lifetime of frog oocytes by feeding them nutrients and triggered apoptosis by mimicking a lack of nutrients.
The oocytes lived longer when provided with the simple sugar building blocks needed to fuel metabolism, "like fattening them up to keep them alive," Kornbluth said. Further detective work revealed the reason why: a molecular pathway involved in metabolizing the sugar is directly linked to an enzyme called caspase-2, which causes apoptosis. Caspases are enzymes that chew up and destroy cells during the apoptosis process.
When the Duke team "fed" the simple sugars to frog eggs and oocytes, they shut off apoptosis. Conversely, preventing eggs from metabolizing these sugars and using the molecular pathway quickly prompted cell death, the researchers found.
The link between an egg's energy stores and the caspase-2 enzyme is especially important because previous studies showed that turning off caspase-2 in mice prevents oocytes from dying, even in response to toxic agents like chemotherapy drugs, said Seth Margolis, Ph.D., a study co-author and postdoctoral researcher in Duke's department of pharmacology and cancer biology. Also, female mice missing the gene to produce caspase-2 are born with an excess number of oocytes.
"We've really demonstrated that caspase-2 is the thing required for oocyte death, and provided a specific molecular mechanism that can keep it shut off," Margolis said.
Collaborators on the study include Mette Jensen, Catherine Herman and Jeffrey Rathmell of Duke, and William Dunphy of the California Institute of Technology.
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