Study Solves Mystery of Human Eggs’ Longevity

Researchers in Spain have discovered the mechanism by which human oocytes can remain dormant for up to 50 years without losing their reproductive capacity. Using a combination of live imaging, proteomic and biochemistry techniques, the team at Centre for Genomic Regulation (CRG) found that immature human egg cells skip a fundamental metabolic reaction thought to be essential for generating energy, and that by altering their metabolic activity in this way, the cells avoid creating reactive oxygen species that can accumulate, damage DNA and cause cell death.

“Humans are born with all the supply of egg cells they have in life. As humans are also the longest-lived terrestrial mammal, egg cells have to maintain pristine conditions while avoiding decades of wear-and-tear,” says Dr. Aida Rodriguez, postdoctoral researcher at the CRG and first author of the study, published in a recent issue of Nature. “We show this problem is solved by skipping a fundamental metabolic reaction that is also the main source of damage for the cell. As a long-term maintenance strategy, it’s like putting batteries on standby mode. This represents a brand new paradigm never before seen in animal cells.”

Human eggs are first formed in the ovaries during fetal development. During the early stages of maturation, immature egg cells known as oocytes are put into cellular arrest, remaining dormant for up to 50 years in the ovaries. Like all other eukaryotic cells, oocytes have mitochondria, which they use to generate energy for their needs during this period of dormancy.

The authors found that mitochondria in both human and Xenopus oocytes use alternative metabolic pathways to generate energy never before seen in other animal cell types. A complex protein and enzyme known as complex I is the usual ‘gatekeeper’ that initiates the reactions required to generate energy in mitochondria. This protein is fundamental, working in the cells that constitute living organisms ranging from yeast to blue whales. However, the researchers found that complex I is virtually absent in oocytes. The only other type of cell known to survive with depleted complex I levels are all the cells that make up the parasitic plant mistletoe.

According to the authors, the findings explain why some women with mitochondrial conditions linked to complex I, such as Leber’s Hereditary Optic Neuropathy, do not experience reduced fertility compared to women with conditions affecting other mitochondrial respiratory complexes. The findings could also lead to 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 cancerous cells while sparing oocytes,” says Dr. Elvan Böke, senior author of the study and Group Leader in the Cell & Developmental Biology program at the CRG.

The researchers plan to continue this line of research and uncover the energy source oocytes use during their long dormancy in the absence of complex I, with one of the aims being to understand the effect of nutrition on female fertility. “One in four cases of female infertility are unexplained – pointing to a huge gap of knowledge in our understanding of female reproduction. Our ambition is to discover the strategies (such as the lack of complex I ) oocytes employ to stay healthy for many years in order to find out why these strategies eventually fail with advanced age,” says Dr. Böke.