As women age, theirstockpile of immature eggs, called oocytes, diminishes through celldeath, eventually leading to infertility. In studies with frog oocytes,the Duke researchers found that the nutrient storehouse, or yolk, playsa key role in regulating the survival of these cells. Depleting thenutrients triggers apoptosis – programmed cell death – and addingnutrients prolongs the life of eggs, they found. The study offerspotential for developing oocyte-protective therapies for womenundergoing chemotherapy, as well as potential targets for improvedinfertility treatments, the researchers said.
"This discoveryprovides a basic science underpinning for understanding the mechanismsof oocyte death and a way to identify potential clinical treatments,"said Sally Kornbluth, Ph.D., senior study author and an associateprofessor of pharmacology and cancer biology at Duke University MedicalCenter.
Adds Leta Nutt, Ph.D., lead author of the study, "Ourwork provides evidence for a metabolic timer in which oocytes that useup their energy stores are fated to die." Nutt is a postdoctoralresearcher in Duke's department of pharmacology and cancer biology.
Theresults appear in the Oct. 7, 2005, issue of Cell. The work wassupported by the National Institutes of Health, the Sidney KimmelFoundation for Cancer Research, the V Foundation for Cancer Researchand the Triangle Community Foundation.
Oocytes are one of the fewcells to rely entirely on internal energy stores, receiving nonutrients from the body. Human oocytes have a relatively small nutrientstockpile compared to the frog oocytes studied by the Duke researchers.
Toexplore the link between energy stores and apoptosis (cell death), theresearchers both extended the lifetime of frog oocytes by feeding themnutrients and triggered apoptosis by mimicking a lack of nutrients.
Theoocytes lived longer when provided with the simple sugar buildingblocks needed to fuel metabolism, "like fattening them up to keep themalive," Kornbluth said. Further detective work revealed the reason why:a molecular pathway involved in metabolizing the sugar is directlylinked to an enzyme called caspase-2, which causes apoptosis. Caspasesare enzymes that chew up and destroy cells during the apoptosis process.
Whenthe Duke team "fed" the simple sugars to frog eggs and oocytes, theyshut off apoptosis. Conversely, preventing eggs from metabolizing thesesugars and using the molecular pathway quickly prompted cell death, theresearchers found.
The link between an egg's energy stores andthe caspase-2 enzyme is especially important because previous studiesshowed that turning off caspase-2 in mice prevents oocytes from dying,even in response to toxic agents like chemotherapy drugs, said SethMargolis, Ph.D., a study co-author and postdoctoral researcher inDuke's department of pharmacology and cancer biology. Also, female micemissing the gene to produce caspase-2 are born with an excess number ofoocytes.
"We've really demonstrated that caspase-2 is the thingrequired for oocyte death, and provided a specific molecular mechanismthat can keep it shut off," Margolis said.
Collaborators on thestudy include Mette Jensen, Catherine Herman and Jeffrey Rathmell ofDuke, and William Dunphy of the California Institute of Technology.
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