Early human oocytes remodel their metabolic activity, which enables them to remain dormant and reproductively viable for decades.
Humans form oocytes during fetal development. These oocytes then undergo cellular arrest and remain dormant in the ovaries for up to 50 years. During dormancy the oocytes maintain mitochondrial activity to generate energy for essential cell processes. This energy generation produces reactive oxygen species (ROS) as by-products. ROS are highly reactive oxygen-containing molecules which are harmful in high concentrations and can damage oocytes causing cell death. A paper published in Nature has revealed that oocytes can alter their metabolic pathways to limit the production of ROS.
'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.' said Dr Aida Rodriguez, postdoctoral researcher at the Centre for Genomic Regulation (CRG) in Barcelona, Spain, and first author of the study. 'We show this problem is solved by skipping 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 batteries on standby mode. This represents a brand new paradigm never before seen in animal cells,'.
The researchers studied Xenopus (African clawed frog) and human oocytes in early- and late-stages of development. Live imaging showed that early human and Xenopus oocytes do not generate any detectable ROS signal.
Mitochondria contain five complexes, I-V, which perform the chemical reactions needed to generate energy in a cell. The researchers inhibited each of these complexes in Xenopus oocytes and found that while early- and late-stage oocytes died upon inhibition of complexes II-V, 78 percent of early-stage oocytes survived if complex I was inhibited, suggesting this complex is not used at this stage of development.
The researchers then examined whether the subunits which make up complex I are depleted in early human oocytes and found that they were either absent or at very low levels. When studying ROS levels and complex I assembly, they found that ROS start to build up as complex I is formed.
These results show that complex I is absent in early human oocytes which limits ROS production and the related cell damage. This metabolic remodelling helps maintain the reproductive capacity of early oocytes for the years in which they remain dormant.
The researchers have proposed that the absence of complex I in early human oocytes could be exploited for other purposes such as 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,' explained senior author Dr Elvan Böke, group leader in the Cell and Developmental Biology programme at the CRG.
These results could have life-changing effects on the quality of life of young women post cancer treatment by avoiding infertility which can result from chemotherapy.