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Egg Cells Maintain Reproductive Longevity by Switching to "Standby Mode"

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Researchers at the Center for Genomic Regulation (CRG) in Barcelona have discovered a mechanism that may explain how immature human egg cells (oocytes) are able to survive for long periods of time without losing their reproductive capacity. The results are published in the journal Nature.

Oocytes must remain healthy for several decades

An oocyte is an immature egg cell (ovum) – the female germ cell involved in reproduction. It is thought that at birth, humans are born with all the egg cells that they will have throughout life. The American College of Obstetricians and Gynecologists estimates that newborns have approximately 1–2 million oocytes, which decreases to 300,000–500,000 at puberty, 25,000 by 37 years of age and approximately 1,000 by 51 years of age.

With the human lifespan being one of the longest of terrestrial mammals, oocytes have to remain dormant for decades while avoiding as much cellular damage as possible in order to maintain their reproductive capacity. Although age-associated reductions in the quality and quantity of oocytes and ova are one of the major risk factors of female infertility, relatively little is known about the mechanisms that oocytes use to maintain their cellular fitness.

Like all cells, dormant oocytes must remain metabolically active so that they can produce essential molecules required to keep the cell viable and functioning – such as amino acids and nucleotides – even when they are not actively growing or dividing. However, the mitochondria within cells, which power metabolism, can also produce damaging molecules called reactive oxygen species (ROS) as by-products. At high enough concentrations, ROS can damage DNA and other molecules, causing toxicity and potentially leading to programmed cell death (apoptosis).

In the new study, researchers set out to understand how oocytes balance their metabolic needs while limiting the production of potentially harmful ROS. Dr. Elvan Böke, senior author of the study and group leader in cell and developmental biology at the CRG, explains, “One in four cases of female infertility are unexplained – this signals that there are many ‘unknown unknowns’ in our knowledge of female reproduction. Our discovery sheds light on the curious problem of how an oocyte can live 20–30 years but retain a youthful cytoplasm.”

Reprogramming mitochondrial metabolism

To carry out their study, researchers in Böke’s laboratory first used oocytes that were in their early and late stages of development, obtained from African clawed frogs (Xenopus laevis) – a readily available model organism. Later, they turned to human early oocytes (also known as primordial oocytes) to test their hypotheses, due to the difficulty of obtaining human samples.

First, cells were labeled with a probe that allowed them to quantify ROS levels, which showed that neither the Xenopus nor the human early oocytes exhibited detectable ROS signals. Additionally, treating oocytes with menadione – a vitamin K precursor that promotes ROS formation – led to cell death in almost 80% of the oocytes, demonstrating just how tightly regulated ROS production must be within these cells to prevent damage.

Next, the researchers investigated the activity of the oocyte mitochondria. These produce ROS as a by-product when generating adenosine triphosphate (ATP), the energy currency that powers the cell. Within mitochondria there are a series of five complexes – named complexes I, II, III, IV and V – which carry out the reactions required to produce ATP in a process known as oxidative phosphorylation. Xenopus oocytes were treated with inhibitors for each of these complexes to determine how important they were for the health of the cells, as the researchers also found that the mitochondrial activity was relatively low. Both early- and late-stage oocytes died when researchers inhibited complexes II to V – however, 78% of early-stage oocytes survived after inhibition of complex I, suggesting that early-stage oocytes do not rely on complex I during oxidative phosphorylation.

Analysis of the proteins that make up each of these mitochondrial complexes showed that the proteins that comprise complex I were inactive and disassembled in early Xenopus oocytes. However, as oocytes matured and became prepared for ovulation, complex I proteins became active and their expression increased, leading to cells producing ROS and becoming sensitive to complex I inhibition.

Together, these results suggest that early oocytes remodel their mitochondrial metabolism to avoid ROS damage in such a way that complex I is no longer necessary for survival, existing in a cellular “standby mode”, and later switch metabolism back when oocytes begin to mature and in turn require more energy. This is a surprising finding according to the researchers, given that the only other cells from similar multi-cellular organisms that are known to exist without functioning mitochondrial complex I belong to the parasitic plant mistletoe. The authors of the study explain that direct biochemical analysis could not be performed in human oocytes to measure complex I activity as, with current technology, this would require oocytes from several thousand donors. Instead, a combination of techniques including proteomics and imaging suggests that complex I is also absent from human early oocytes as well as in Xenopus oocytes.

Improving our understanding of female fertility

Overall, the results of this study show that early oocytes limit ROS-mediated damage by deactivating mitochondrial complex I – one of the main cellular generators of ROS – to maintain their longevity. The authors state that, to their knowledge, this is the first evidence of a physiological animal cell type that exists without functioning mitochondrial complex I.

Böke and colleagues are eager to explore these findings further: “We plan to investigate the mechanisms that allow oocytes to survive without complex I. We are especially interested in the energy sources dormant oocytes rely on in the ovary. This line of research will have major implications linking diet and nutrition to female fertility,” Böke explains. “For example, now we can start checking the levels of complex I subunits in immature oocytes of women with unexplained fertility problems and see whether we can explain some of these problems,” She concludes.

Dr. Elvan Böke was speaking to Sarah Whelan, Science Writer for Technology Networks.

ReferenceRodríguez-Nuevo A, Torres-Sanchez A, Duran JM, De Guirior C, Martínez-Zamora MA, Böke E. Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I. Nature. 2022:1-6. doi: 10.1038/s41586-022-04979-5