News | Study Reveals New Mechanism Behind Oocyte Longevity
Oocytes are immature egg cells that develop before birth in nearly all female mammals. Future generations depend on this finite reserve surviving without damage for many years. This can last up to 18 months in mice and nearly half a century in humans—the average time from birth to menopause. How these cells achieve such longevity has long remained unknown.
Researchers at the Centre for Genomic Regulation (CRG) in Barcelona discovered a new mechanism explaining how oocytes remain intact for decades despite wear and damage that would disable other cell types. Published today in Cell, the findings open a new frontier in research on unexplained infertility.
The researchers examined protein aggregates—clusters of misfolded or damaged proteins. If uncontrolled, these harmful substances accumulate in the cytoplasm and become highly toxic. Protein aggregates are known to build up in neurons and are associated with several neurodegenerative diseases. Cells usually manage them by breaking them down with specialized enzymes. They can also divide into two new cells, concentrating the aggregates in one cell and sparing the other.
Oocytes are different. Their longevity means they cannot disperse toxic material through cell division. Constantly breaking down protein aggregates is not viable because it requires substantial energy that may not be available. Oocytes must also contribute their entire cytoplasm to the embryo after joining with sperm, so they tend to reduce metabolic activity. This avoids by-products that could damage maternal DNA and affect future reproductive success, but makes oocytes especially vulnerable to misfolded or damaged proteins.
Dr. Elvan Böke, head of CRG's Oocyte Biology and Cellular Dormancy group, explained: "Compared with thousands of papers on protein aggregation in neurons, there is almost no research on how mammalian oocytes cope with it, even though they face the same problems of longevity and not dividing."
"We wanted to explore how oocytes handle these misfolded or damaged proteins," Dr. Böke added.
A Patrolling "Cleanup Crew"
Dr. Böke's team, led by Dr. Gabriele Zaffagnini, collected thousands of immature oocytes, mature eggs, and early embryos from adult mice. Using special dyes and live-cell imaging, they observed protein aggregates in real time. They also used electron microscopy to examine nanoscale details inside the cells. The work took five and a half years.
The researchers discovered specialized structures in oocytes that they named EndoLysosomal Vesicular Assemblies (ELVAs). About 50 per oocyte move through the cytoplasm, capturing and containing protein aggregates so they remain harmless. Researchers describe ELVAs as "super-organelles" because they are networks of many different cellular components working as one unit.
The study identified a critical point during oocyte maturation, when an oocyte becomes a mature egg ready for ovulation and possible fertilization. ELVAs moved to the cell surface and broke down protein aggregates, effectively deep-cleaning the cytoplasm. This was the first observation of the oocyte's unique strategy for clearing protein aggregates.
"An oocyte must give all its cytoplasm to the embryo at fertilization, so it cannot allow waste to accumulate and pose an existential risk to its function. ELVAs act like a sophisticated waste-disposal network or cleanup crew, patrolling the cytoplasm so no aggregates float freely. They contain the aggregates until the oocyte is ready to dispose of them all at once. It is an effective, energy-efficient strategy," Dr. Gabriele Zaffagnini explained.
Protein Aggregates May Cause Infertility
Fertility declines with age, and poor oocyte quality is a leading cause of female infertility. Infertility rates are also rising globally, partly because of delayed childbearing. Understanding how oocytes stay healthy and why these strategies fail with age is essential to understanding unexplained infertility and developing new treatments.
The findings suggest that protein aggregates may impair egg and embryo quality. Experimentally blocking ELVAs from degrading protein aggregates during oocyte maturation produced defective eggs. When researchers intervened to "force" embryos to inherit aggregated proteins, 3/5 (60%) failed to complete early development.
Dr. Böke concluded: "Historically, many studies have focused on one small aspect of declining oocyte quality: meiosis and aneuploidy. However, a recent review of 11,000 embryo transfers showed that other unknown factors mainly drive the age-related decline in female fertility. Our research opens an exciting direction for exploring whether protein degradation and its regulation in oocytes can explain the age-related decline in embryo health."
Neurons are another long-lived, nondividing cell type that must manage protein aggregates. Accumulation of these harmful substances is associated with several neurodegenerative diseases, including Alzheimer's disease. Do ELVA-like structures also exist in neurons and other cell types? This study opens avenues for research beyond reproduction.
News | Study Reveals New Mechanism Behind Oocyte Longevity
News | Study Reveals New Mechanism Behind Oocyte Longevity
Oocytes are immature egg cells that develop before birth in nearly all female mammals. Future generations depend on this finite reserve surviving without damage for many years. This can last up to 18 months in mice and nearly half a century in humans—the average time from birth to menopause. How these cells achieve such longevity has long remained unknown.
Researchers at the Centre for Genomic Regulation (CRG) in Barcelona discovered a new mechanism explaining how oocytes remain intact for decades despite wear and damage that would disable other cell types. Published today in Cell, the findings open a new frontier in research on unexplained infertility.
The researchers examined protein aggregates—clusters of misfolded or damaged proteins. If uncontrolled, these harmful substances accumulate in the cytoplasm and become highly toxic. Protein aggregates are known to build up in neurons and are associated with several neurodegenerative diseases. Cells usually manage them by breaking them down with specialized enzymes. They can also divide into two new cells, concentrating the aggregates in one cell and sparing the other.
Oocytes are different. Their longevity means they cannot disperse toxic material through cell division. Constantly breaking down protein aggregates is not viable because it requires substantial energy that may not be available. Oocytes must also contribute their entire cytoplasm to the embryo after joining with sperm, so they tend to reduce metabolic activity. This avoids by-products that could damage maternal DNA and affect future reproductive success, but makes oocytes especially vulnerable to misfolded or damaged proteins.
Dr. Elvan Böke, head of CRG's Oocyte Biology and Cellular Dormancy group, explained: "Compared with thousands of papers on protein aggregation in neurons, there is almost no research on how mammalian oocytes cope with it, even though they face the same problems of longevity and not dividing."
"We wanted to explore how oocytes handle these misfolded or damaged proteins," Dr. Böke added.
A Patrolling "Cleanup Crew"
Dr. Böke's team, led by Dr. Gabriele Zaffagnini, collected thousands of immature oocytes, mature eggs, and early embryos from adult mice. Using special dyes and live-cell imaging, they observed protein aggregates in real time. They also used electron microscopy to examine nanoscale details inside the cells. The work took five and a half years.
The researchers discovered specialized structures in oocytes that they named EndoLysosomal Vesicular Assemblies (ELVAs). About 50 per oocyte move through the cytoplasm, capturing and containing protein aggregates so they remain harmless. Researchers describe ELVAs as "super-organelles" because they are networks of many different cellular components working as one unit.
The study identified a critical point during oocyte maturation, when an oocyte becomes a mature egg ready for ovulation and possible fertilization. ELVAs moved to the cell surface and broke down protein aggregates, effectively deep-cleaning the cytoplasm. This was the first observation of the oocyte's unique strategy for clearing protein aggregates.
"An oocyte must give all its cytoplasm to the embryo at fertilization, so it cannot allow waste to accumulate and pose an existential risk to its function. ELVAs act like a sophisticated waste-disposal network or cleanup crew, patrolling the cytoplasm so no aggregates float freely. They contain the aggregates until the oocyte is ready to dispose of them all at once. It is an effective, energy-efficient strategy," Dr. Gabriele Zaffagnini explained.
Protein Aggregates May Cause Infertility
Fertility declines with age, and poor oocyte quality is a leading cause of female infertility. Infertility rates are also rising globally, partly because of delayed childbearing. Understanding how oocytes stay healthy and why these strategies fail with age is essential to understanding unexplained infertility and developing new treatments.
The findings suggest that protein aggregates may impair egg and embryo quality. Experimentally blocking ELVAs from degrading protein aggregates during oocyte maturation produced defective eggs. When researchers intervened to "force" embryos to inherit aggregated proteins, 3/5 (60%) failed to complete early development.
Dr. Böke concluded: "Historically, many studies have focused on one small aspect of declining oocyte quality: meiosis and aneuploidy. However, a recent review of 11,000 embryo transfers showed that other unknown factors mainly drive the age-related decline in female fertility. Our research opens an exciting direction for exploring whether protein degradation and its regulation in oocytes can explain the age-related decline in embryo health."
Neurons are another long-lived, nondividing cell type that must manage protein aggregates. Accumulation of these harmful substances is associated with several neurodegenerative diseases, including Alzheimer's disease. Do ELVA-like structures also exist in neurons and other cell types? This study opens avenues for research beyond reproduction.
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