Research on human oocytes reveals how these cells remain in a dormant state in the ovaries for decades, remaining healthy and without losing their reproductive capacity.
The study is the work of the team led by Aida Rodríguez-Nuevo, from the Center for Genomic Regulation (CRG) in Barcelona.
The study results indicate that immature human eggs skip a critical metabolic reaction to generate energy.
By altering their metabolic activity, cells prevent the creation of reactive oxygen species, harmful molecules that can build up, damage DNA and cause cell death. The findings explain how human oocytes remain dormant in the ovaries for up to 50 years without losing their reproductive capacity.
“We are born with the entire supply of eggs that we will have in life. As humans are also the longest living land mammals, the eggs must be kept in pristine condition and avoid decades of wear and tear. We show that this problem is solved by bypassing a fundamental metabolic reaction that is also the main source of damage to the cell. As a long-term maintenance strategy, it’s like putting the engine in neutral. This represents a new paradigm never seen before in animal cells”, says Dr. Aida Rodríguez, postdoctoral researcher at the CRG and first author of the study.
Human eggs are first formed in the ovaries during fetal development, passing through different stages of maturation. During the early stages, immature eggs (known as oocytes) remain in a state of cellular arrest, remaining dormant for up to 50 years in the ovaries. Like all eukaryotic cells, oocytes contain mitochondria, the cell’s batteries or engine, which they use to generate energy for their needs during this latency period.
Using a combination of live imaging, proteomic and biochemical techniques, the study authors found that mitochondria in human and Xenopus frog oocytes use alternative metabolic pathways to generate energy. These alternative pathways have never before been seen in other types of animal cells.
An enzyme complex known as complex I is the usual entry point that initiates the reactions necessary to generate energy in the mitochondria. This enzyme is essential, and it works in the cells that make up living organisms ranging from yeast to blue whales. However, the scientific team found that complex I is virtually absent in oocytes. The only other case known to survive with reduced levels of complex I are all the cells that make up the parasitic mistletoe plant.
Living cells of a human follicle, showing the granulosa cells in the outer layer, which support the oocyte contained within. The activity of reactive oxygen species is shown in red. The researchers observed reactive oxygen species activity in granulosa cells, but it is virtually absent in the oocyte. (Images: Aida Rodriguez/Nature. CC BY)
According to the study authors, the research explains why some women with complex I-linked mitochondrial conditions, such as Leber hereditary optic neuropathy, do not experience reduced fertility compared with women with conditions affecting other mitochondrial respiratory complexes.
The findings could also lead to new strategies to help preserve ovarian reserves in patients undergoing cancer treatment. “Complex I inhibitors have previously been proposed as a cancer treatment. If these inhibitors show promise in future studies, they could potentially target cancer cells without affecting oocytes,” explains Dr. Elvan Böke, lead author of the study and group leader in the Cell and Developmental Biology program at the CRG.
Oocytes are very different from other cell types because they have to balance longevity with function. The researchers plan to continue with this line of research and discover exactly what the source of energy used by the oocytes is like during their long latency stage in the absence of complex I, one of the objectives being to better understand the effect of nutrition on fertility. feminine.
“One in four cases of female infertility is unexplained, pointing to a large knowledge gap in our understanding of female reproduction. Our ambition is to discover the strategies (such as the lack of complex I) that oocytes use to stay healthy for many years in order to find out why these strategies eventually fail with old age”, concludes Dr. Böke.
The study is titled “Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I.” And it has been published in the academic journal Nature. (Source: CRG)