Women are born with all the eggs they will have throughout their lives to become pregnant, since after birth no new eggs are produced and at a certain time, which coincides with menopause, the ovarian reserve is exhausted and loses reproductive capacity. That is why it is so important that the oocytes – which are the immature eggs – remain healthy for decades to fulfill their mission. Now a study has discovered how they do it.
During fetal development, the ovules are formed in the ovaries and during the first phases of maturation, the oocytes are in a state of cellular arrest and remain in a latent state –inactive– in the ovaries for a period of up to 50 years, without losing their reproductive capacity. That is, they put “the engine in neutral” to maintain its functionality for decades.
The oocytes contain mitochondria –considered the engine of the cell– and use them to generate energy and meet their needs during this latency period. The new research, carried out by a scientific team from the Center for Genomic Regulation (CRG), has discovered that immature human eggs skip a key metabolic reaction to generate energy. By modifying their metabolic activity, these cells prevent the development of reactive oxygen species, which are harmful molecules that can accumulate, damage DNA and cause cell death.
“Humans are born with the full supply of eggs they have in life. Since humans are also the longest-living land mammals, the eggs must be kept in pristine condition and prevent 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”, explained Dr. Aida Rodríguez, postdoctoral researcher at the CRG and first author of the study.
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 that had never been seen before in other types of cells. animal cells.
“Humans are born with the full supply of eggs they have in life. As they are also the longest living land mammals, the eggs must be kept in pristine condition and avoid decades of wear and tear.”
An enzyme complex called complex I is the usual entry point that initiates the reactions needed to generate energy in the mitochondria. This enzyme is essential and acts on the cells that make up living organisms, from yeast to blue whales. However, the scientific team found that complex I is virtually absent in oocytes. Only one other living being is known to maintain itself with reduced levels of complex I and they are the cells that make up the mistletoe, a parasitic plant.
New strategies to preserve the ovarian reserve
The authors say the study findings explain why the fertility of some women with complex I-linked mitochondrial conditions, such as Leber hereditary optic neuropathy, is not reduced compared with women with conditions that influence other mitochondrial respiratory complexes.
The results, which have been published in Nature, could also facilitate the development of new strategies that help preserve the ovarian reserves of 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 have to balance longevity with function, which makes them very different from other cell types. The researchers intend to continue with this line of research and discover the source of energy used by the oocytes during their long latency stage in the absence of complex I, and one of their objectives is to discover the effects of nutrition on female fertility.
“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 to find out why these strategies ultimately fail with old age”, concludes Dr. Böke.
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