Oocytes cleverly evade toxic proteins to maintain long-term female fertility

Researchers at the Centre for Genomic Regulation (CRG) in Barcelona have discovered a new mechanism which explains how oocytes remain in pristine conditions for decades without succumbing to the wear and tear that would cause other cell types to fail. The research published in the journal Cell,represents a new frontier to explore the unexplained causes of infertility.

Oocytes are immature egg cells that develop in almost all female mammals before birth. The propagation of future generations depends on this finite reserve of cells surviving for many years without incurring damage and can last almost half a century, the average time between birth and menopause.

The researchers studied protein aggregates, which are clusters of misfolded or damaged proteins known for their toxic effects. These aggregates accumulate in the cytoplasm and are associated with various neurodegenerative diseases. Cells typically manage them by enzymatically breaking them down or segregating them during cell division. However, oocytes, responsible for contributing their entire cytoplasm to an embryo after fertilization, reduce their metabolic activity to minimize the generation of harmful by-products that could compromise maternal DNA and future reproductive success. As a result, oocytes are particularly sensitive to misfolded or damaged proteins.

Dr.Böke's team, led by Dr. Gabriele Zaffagnini, extensively examined thousands of immature oocytes, mature eggs, and early embryos from adult mice. Using special dyes and live-cell imaging, they observed protein aggregate behavior in real-time. Electron microscopy provided nanoscopic insights within cells, culminating in the identification of EndoLysosomal Vesicular Assemblies (ELVAs). These structures, approximately 50 per oocyte, move throughout the cytoplasm, capturing and neutralizing protein aggregates. ELVAs are dubbed a "superorganelle" due to their diverse cellular components operating cohesively as a single unit.

The study’s findings revealed a crucial moment during the oocyte maturation stage which is when an oocyte converts into a mature egg, preparing for ovulation and possible fertilisation. During this stage, the researchers observed ELVAs moving towards the cell's surface and breaking down the protein aggregates, essentially deep-cleaning the cytoplasm.

“An oocyte must donate all its cytoplasm to the embryo at fertilisation, so it cannot afford for garbage to accumulate, which would pose an existential risk for its function. In that sense, ELVAs are like a sophisticated waste disposal network or clean-up crew, patrolling the cytoplasm to ensure no aggregates are freely floating. ELVAs keep these aggregates in a confined environment until the oocyte is ready to dispose of them in one fell swoop. It’s an effective and energy-efficient strategy,” saidDr.Zaffagnini, postdoctoral researcher at the Centre for Genomic Regulation.

Reference: Gabriele Zaffagnini, Shiya Cheng, Marion C. Salzer, Barbara Pernaute, Juan Manuel Duran, Manuel Irimia, Melina Schuh, Elvan Böke. Mouse oocytes sequester aggregated proteins in degradative super-organelles. Cell, 2024; DOI: 10.1016/j.cell.2024.01.031