The ova They develop before birth in almost all female mammals. In fact, reproduction depends on this finite reserve immature eggs Survive for many years without damage. While in mice it can be a period of up to eighteen months, in humans it can take almost half a century (the average time to menopause).
Until now, it has been a mystery how cells achieve this feat longevity. A team from the Center for Genomic Regulation (CRG) in Barcelona has discovered a new mechanism that explains how eggs remain in perfect condition for decades without undergoing the wear and tear that would occur with other cell types.
The results, published in the journal cellrepresent a new frontier for Explore the unexplained causes of infertility.
The study focuses on the Protein aggregatesThese are groups of misfolded or damaged proteins. If these pollutants are not controlled, they accumulate in the cytoplasm and have highly toxic effects. Therefore, they are stored in neurons and their effects are associated with several neurodegenerative diseases.
Cells typically process aggregates by breaking them down with special enzymes. They can also divide into two new cells, concentrating the aggregates in one of the cells without affecting the other. But eggs are not like other cells and are particularly sensitive to the effects of these misfolded or damaged proteins.
However, “in contrast to the tens of thousands of papers on protein aggregation in neurons, the way mammalian eggs deal with it remains essentially unexplored, even though they share the same problem of being long-lived and not dividing.””, Explain it Elvan BökeHead of the oocyte biology and cellular latency group at the CRG and author of the study.
Necessary cleaning equipment
The Böke team led by Gabriele Zaffagnini, began collecting thousands of immature eggs, mature eggs and early developing embryos from mice. Using special dyes, they observed how protein aggregates behave in real time using a special imaging technique.
The experts discovered special structures in the eggs, which they called endolysosomal vesicular assemblies, or ELVAs, after their English acronym. These structures (about 50 per egg) migrate through the cytoplasm, where they capture and hold onto protein aggregates, rendering them harmless.
The study revealed a crucial moment during the egg’s maturation phase: when it develops into a mature egg, preparing for ovulation and possible fertilization.
At the time of fertilization, an egg cell must donate all of its cytoplasm to the embryo so that no waste can accumulate that would pose an existential threat to its function.
At this stage, ELVAs were observed to move toward the cell surface and break down protein aggregates, essentially thoroughly cleaning the cytoplasm. This is the first observation of the unique strategy that eggs use to get rid of protein aggregates.
“An egg cell must donate all of its cytoplasm to the embryo at the time of fertilization so that it cannot allow waste to accumulate that would pose an existential risk to its function.” In this sense, ELVAs are like a sophisticated waste disposal network or cleaning team, that monitors the cytoplasm to ensure that there are no free-floating aggregates,” says co-author Zaffagnini.
“ELVAs keep these aggregates in a confined environment until the egg is ready to get rid of them all at once. From an energy perspective, it is an effective and efficient strategy,” he adds.
ELVAs photographed under the microscope. This super organelle travels through the cytoplasm and captures and retains toxic protein aggregates to protect the eggs. / Weihua Leng/MPI-CBG
Significance in infertility
Infertility rates are increasing worldwide, with delayed births being one of the contributing factors. To understand the unknown causes of this problem and to open up new treatment options, it is important to understand how eggs stay healthy and why these strategies fail with age.
The results of the study suggest that the presence of protein aggregates could affect the quality of both the egg and the embryo.
When the authors eliminated the ability of ELVAs to break down protein aggregates during the egg maturation process, defective eggs resulted. Furthermore, when the team caused the embryos to inherit aggregated proteins, 60% failed to complete very early stages of development.
“A recent study of eleven thousand embryo transfers has shown that the decline in female fertility with increasing age is strongly influenced by as yet unknown factors. “Our study opens a future direction to investigate whether protein degradation and problems in its regulation in eggs could explain the time-related deterioration in embryonic health,” concludes Böke.
Reference:
Zaffagnini et al. “Cell, 2024.