Immature eggs, also known as oocytes, are formed in most female mammals before birth. These cells are essential for the continuity of the species and must remain healthy for many years to effectively carry out their reproductive function. In mice, this period can last up to 18 months, while in women, it can last about half a century, which is the average interval between birth and menopause. How oocytes achieve this impressive longevity has long been an enigma.
Now, researchers from the Center for Genomic Regulation (CRG) in Barcelona have identified a novel mechanism that explains the way in which oocytes remain intact for decades without suffering the deterioration that affects other types of cells. This discovery, recently published in the journal Cell, opens a new path to investigate unknown causes of infertility.
It is estimated that the ovarian reserve of women at birth is between one and two million oocytes, of which around 400,000 can reach the age of puberty. During the reproductive stage, the woman will ovulate a maximum of between 400 and 500 times, and at each ovulation hundreds of oocytes will be ready to be fertilized, but only one of them will be selected and the rest will be lost. When the oocytes are depleted, the woman enters the menopause phase.
This means that oocytes have to live for decades (at least half a century between birth and menopause in the case of the human species) without suffering damage that could prevent their future fertilization. It is known that fertility decreases with age and that poor oocyte quality is the main cause of female infertility. Understanding how oocytes stay healthy and why these strategies fail with age is crucial to understanding unexplained causes of infertility and developing new treatments.
The secret of oocyte longevity
These scientists studied protein clusters, formed by misfolded or damaged proteins that, if not controlled, can be harmful, as they are deposited in the cytoplasm and cause toxic effects. It is known that this type of accumulation affects neurons and is related to various neurodegenerative diseases. Normally, cells get rid of these buildups by cell division or by breaking them down with enzymes.
However, oocytes do not function like other cells because their longevity prevents them from eliminating harmful substances by dividing. Furthermore, constantly breaking down misfolded proteins is not sustainable as it consumes a lot of energy. Oocytes must also transfer their entire cytoplasm to the embryo after fertilization, so they reduce their metabolic activity to avoid generating harmful byproducts that could harm maternal DNA and future reproductive success. This makes oocytes especially sensitive to damaged or misfolded proteins.
“Unlike the thousands of studies on protein accumulation in neurons, the way in which mammalian oocytes handle this problem has been little studied, despite facing the same challenge of longevity and lack of cell division,” explains the Dr. Elvan Böke, leader of the oocyte biology and cell latency group at the CRG and senior author of the study. “We wanted to understand how oocytes handle these problematic proteins,” he adds.
Dr. Böke’s team, led by Dr. Gabriele Zaffagnini, collected thousands of immature oocytes, mature eggs and early embryos from mice. Using special dyes, they observed the behavior of the accumulated proteins in real time using live cell imaging techniques. They also applied electron microscopy to examine the cells’ nanoscopic components in detail, a task that took five and a half years to complete.
They discovered special structures in the oocytes, called endolysosomal vesicular assemblies (or ELVAs for their acronym in English). These structures, about 50 per oocyte, move through the cytoplasm, capturing and neutralizing the accumulated proteins. ELVAs function as a “superorganelle,” a network of several cellular components that operate as a unit.
“Our research offers a promising direction to explore whether problems in protein degradation and its regulation in oocytes could explain age-related decline in embryonic health.”
During the maturation of the oocyte into a mature egg, the researchers observed that ELVAs move to the surface of the cell and break down accumulated proteins, thoroughly cleaning the cytoplasm. This is the first time that this unique strategy has been observed in oocytes to eliminate accumulated proteins.
Understand the unexplained causes of infertility to treat them
The results of the study suggest that accumulated proteins can affect both the quality of the egg and the embryo. By preventing ELVAs from degrading these proteins during oocyte maturation, defective eggs were formed. Furthermore, when embryos inherited accumulated proteins, 60% did not complete early stages of development.
“Many studies have focused on limited aspects of declining oocyte quality, such as meiosis and euploidy. However, a recent analysis of eleven thousand embryo transfers showed that other unknown factors significantly influence declining oocyte quality. female fertility with age. Our research offers a promising direction to explore whether problems in protein degradation and its regulation in oocytes could explain the age-related decline in embryonic health,” concludes Dr. Böke.
Neurons, another type of long-lived cell that does not divide and experiences similar problems with protein buildup, is linked to neurodegenerative diseases such as Alzheimer’s. Could ELVA-like compartments exist in neurons and other cell types? This study opens new research possibilities beyond the field of reproduction.
Rocío Núñez Calonge, embryologist, scientific director of the UR International Group and professor in the Master of Reproduction at the Complutense University and Spanish Fertility Society, who has not participated in the study, has pointed out its limitations in statements to SMC Spain: “There are still numerous doubts, which the authors themselves raise. Could compartments similar to ELVA exist in other types of cells? It has been postulated that a similar mechanism could occur in neurons. But the way in which these long-lived cells, oocytes and neurons, transport their protein aggregates to specialized compartments and regulates their degradation, and whether this really happens in neurons remains future avenues of research to explore.”
And he adds: “The main limitation is that it has been studied in mouse oocytes and we must check if the same thing really happens in humans. In the article it is compared with neurons because they share the similarity with oocytes of not dividing and being long-lived, but the objective of the study and what they focus on is oocytes and their future application in cases of female infertility. I would not go into, as in the case of the press release, talking about Alzheimer’s. In fact, in the article doesn’t even mention it.”
Source: Center for Genomic Regulation (CRG) of Barcelona
