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Scientists identify a key cause of female infertility

Misbehaving mitochondria might cause female infertility

2023-12-13
(Press-News.org) Infertility affects around 48 million couples worldwide and can have various causes. In mammals, including humans, eggs are produced in the ovary. When this process goes wrong, it can lead to female infertility. One example of this is premature ovarian insufficiency, which is characterised by problems with egg production before the age of 40. Up to 3.7% of females experience infertility as a result of this condition, and around 30% of cases are due to genetic variations. Professor Kehkooi Kee, from Tsinghua University, China, who helped lead the study, has been investigating this condition for several years. “In 2019, our collaborators, Professor Li’s team, encountered a family with premature ovarian insufficiency in which changes to a gene called Eif4enif1 appeared to be responsible for the disease,” said Professor Kee. The researchers decided to reproduce this genetic change in mice to try to understand how it affects human infertility. They show that the eggs of these mice are affected by changes to their mitochondria – the powerhouses of the cell – and publish this new discovery in the journal Development on 13 December 2023.

The researchers used CRISPR to introduce the genetic change in the mice. They allowed these mice to grow up and then compared their fertility with the fertility of mice whose DNA had not been edited. Yuxi Ding, the first author and a MD/PhD student who led the study, found that the average number of total follicles (the tiny sacs that contain developing eggs) was reduced by approximately 40% in older and genetically edited mice (the average pup number in every litter was reduced by 33%. Importantly, when grown in a dish, about half of the eggs that were fertilised did not survive beyond the early stages of development. This demonstrated that, just like the human patients, these mice were experiencing problems with fertility.

When the researchers studied the eggs from these mice under the microscope, they noticed something unusual about their mitochondria. Mitochondria produce the energy that cells, including egg cells, need. Mitochondria are usually evenly distributed throughout the egg, but the mitochondria in eggs from mice with the genetic variation were clustered together. “We were actually surprised by the differences in the mitochondria,” said Professor Kee. “At the time we were doing this research, a link between Eif4enif1 and mitochondria had not been seen before.”

It seems likely that these misbehaving mitochondria are contributing to the fertility problems in these mice, leading the researchers to propose that restoring proper mitochondrial behaviour might improve fertility. This study provides direction for future research in human infertility, such as establishing whether mitochondrial defects are also found in the eggs of human patients with premature ovarian insufficiency and whether these same mitochondrial defects are observed in embryos after the eggs are fertilised. In addition, testing whether restoring the normal distribution of mitochondria improves fertility could become a new treatment strategy. “Our research suggests that rescuing oocyte mitochondria abnormality could be a potential therapeutic target for clinical infertility patients with genetic variants,” says Professor Kee.

 

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IF REPORTING THIS STORY, PLEASE MENTION DEVELOPMENT AS THE SOURCE AND, IF REPORTING ONLINE, PLEASE CARRY A LINK TO: https://journals.biologists.com/dev/article-lookup/DOI/10.1242/dev.202151 

ADDITIONAL INFORMATION: Kehkooi Kee, PhD, is a Tenured Professor at the School of Medicine, Tsinghua University, China. Yuxi Ding is currently a visiting scholar at the University of Cambridge.

REFERENCE: Ding, Y., He, Z., Sha, Y., Kee, K., Li, L. (2023). Eif4enif1 haploinsufficiency disrupts oocyte mitochondrial dynamics and leads to subfertility. Development, 150, dev202151 doi: 10.1242/dev.202151

The story is COPYRIGHTED. Therefore, advance permission is required before any and every reproduction of each article in full. Please contact: permissions@biologists.com.

THIS ARTICLE IS EMBARGOED UNTIL Wednesday, 13th December 2023, 16:00 HRS ET (21:00 HRS GMT)

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[Press-News.org] Scientists identify a key cause of female infertility
Misbehaving mitochondria might cause female infertility