Melina Shu “I have been fascinated by ovarian germ cells, or oocytes, since I started my graduate studies in 2004.”[I] “We realized that very little was known about these important cells, which are important for reproduction and the creation of new life,” she said. Schuh, now a biochemist at the Max Planck Institute for Multidisciplinary Science, wonders how oocytes formed before birth can remain functional for decades, and is interested in the understudied factors that may lead to the ultimate decline of these cells. .
In a recent study, Schuh and her team showed that cells in the mammalian ovary contain: Very long-lived protein.1 The research results are natural cell biologyWe shed light on adaptations that help maintain oocytes with minimal damage throughout the reproductive life of female animals and provide clues to the decline in fertility in aged ovaries.
“The biology of extremely long-lived proteins in aging has been known for a long time, but this paper is the first to carefully characterize the nature and identity of these proteins in the ovary,” he said. Ray RayThe reproductive biologist at the University of Missouri School of Medicine was not involved in the study. Making new proteins carries the risk of making mistakes, which the oocytes cannot afford, she added. “Because in the end, you will be supporting a new life.”
report long-lived protein complex In oocytes, Schuh wondered about the proliferation of this phenomenon and whether protein lifetimes play a functional role in maintaining these cells.2 To determine how long the protein could persist in oocytes, Schuh and her team fed pregnant female mice a diet containing amino acids containing heavy carbon isotopes. These mice incorporated this heavy element into their proteins with their offspring in utero. When the animals gave birth, scientists switched them to a diet containing lighter carbon isotopes. This strategy means that proteins made by pups before the diet change will contain heavy carbons, and proteins synthesized later will contain lighter versions.
The researchers then collected oocytes from these pups when they reached puberty and were eight weeks old. Mass spectrometry analysis of these cells revealed that nearly 10% of the proteins were made before the mice were born. Long-lived proteins belong to various cellular components, such as mitochondria, ribosomes, and chromatin, and have been implicated in functions such as metabolism and DNA repair.
The ovary is composed of cells other than oocytes, such as stromal cells and meningeal cells, which play an essential role in reproductive ability. The team wondered whether these cells also contained long-lived proteins. They analyzed proteins in the ovaries of mice up to 15 months of age, which is the older age of the mice. Mathematical modeling showed that more than 10% of proteins have half-lives of more than 100 days, and most remain in the ovaries for most of the animal’s life. By comparison, less than 1% of proteins in cartilage, brain and muscle had such a long lifespan. These long-lived ovarian proteins have essential functions in structures such as mitochondria and the cytoskeleton and in processes such as protein homeostasis and chromatin maintenance. RNA sequencing revealed that in addition to oocytes, a subset of somatic cells in the ovary also contain such long-lived proteins.
Next, the researchers wondered how these proteins could persist for so long. To determine whether altered protein homeostasis played a role, they tested whether aged oocytes contained aggregates of misfolded proteins. Microscopic examination showed that no such aggregates were found in aged oocytes. The researchers also found that age did not reduce the activity of the proteasome, a complex that breaks down misfolded proteins to maintain intracellular protein homeostasis.
Analysis of protein abundance in ovaries revealed an abundance of antioxidants and chaperones that aid protein folding, suggesting long-term retention of proteins by preventing them from misfolding and protecting them from oxidative damage.
To understand the impact of ovarian aging on these long-lived proteins, the researchers tested their abundance in the ovaries of mice at several time points throughout their lifespan, from 1 day to 11.5 months of age. Mass spectrometry revealed that ovarian aging is associated with a decline in many long-lived proteins. This results in extensive remodeling of the ovarian protein landscape, ultimately leading to a gradual decline in fertility after the third month of life in mice.
The discovery of long-lived proteins in the ovaries was not entirely unexpected, Schuh said. “But it was surprising that so much protein persisted for such a long period of time,” she said. Her team set out to examine some of these long-lived proteins to understand why they are not broken down more often and what implications their longevity has functionally.
“These results are important for understanding human ovarian biology and ovarian aging, but they speak against designing medical treatments to delay ovarian aging or improve egg quality based on these results,” Lei said. This is primarily because human ovarian biology is more complex than that of mice, she explained.
“how [these results] “We don’t know yet if there is a direct connection to humans,” Schuh agreed. But she hopes human ovarian proteins may also be long-lasting. Although it’s difficult to study this in humans at the moment, “it would be really interesting to extend this to humans one day,” she said.
