The mitochondria of immature human eggs function differently than those of other cells, according to a new study by researchers at the Centre for Genomic Regulation (CRG) in Barcelona. Specifically, one of the main energy-generating complexes in these mitochondria, known as complex I, is suppressed. The researchers found the same thing in immature eggs from frogs (Xenopus), noting that this is only known cell type in animals without a functional complex I.

The study was led by Elvan Böke, PhD, a group leader at the CRG. Their work is published in an article in the journal Nature:Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I.”

Immature eggs, or oocytes, undergo different stages of maturation in the ovaries. At an early stage, they go into cellular arrest, remaining dormant for up to 50 years. Like all other eukaryotic cells, oocytes have mitochondria that they use to generate energy.

Complex I is the first enzyme in the series of metabolic reactions—known as the electron transport chain—that generate energy in the mitochondria. This protein complex is considered fundamental, working in the cells that constitute living organisms ranging from yeast to blue whales.

Using a combination of live imaging, proteomic, and biochemistry techniques, the team studied both human and Xenopus oocytes and found that complex I is virtually absent in both. The only other type of cell known to survive with depleted complex I levels are the cells that make up the parasitic plant mistletoe. This makes oocytes the only known animal cell type without a functional complex I.

Complex I produces reactive oxygen species (ROS), which are harmful molecules that can accumulate, damage DNA, and stress cells. By altering their metabolic activity to suppress complex I, the oocytes avoid ROS. The findings explain how human egg cells remain dormant in ovaries for decades without losing their reproductive capacity.

Reactive Oxygen Species
A human follicle, showing granulosa cells on the outer layer, which support the oocyte, contained within. The researchers observed reactive oxygen species (ROS; red) in the granulosa cells, but ROS activity was virtually absent in the oocyte. [Aida Rodriguez/Nature]

“Humans are born with all the supply of egg cells they have in life,” explained Aida Rodríguez-Nuevo, PhD, postdoctoral researcher at the CRG and first author of the study. “As humans are also the longest-lived terrestrial mammal, egg cells have to maintain pristine conditions while avoiding decades of wear-and-tear. We show this problem is solved by skipping a fundamental metabolic reaction that is also the main source of damage for the cell.”

According to the authors of the study, the research explains 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 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 more fully understand female fertility.

“One in four cases of female infertility are unexplained—highlighting the many ‘unknown unknowns’ in our understanding of female reproduction,” said Böke. “We can now start checking the levels of complex I subunits in immature oocytes of women with unexplained fertility and see whether we can account for some of these problems.”

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,” Böke explained.

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