By Phyllis Leppert
Reproductive scientists have studied for decades what mechanisms are involved in the decades-long dormancy of primordial oocytes. During fetal development in a female embryo these primordial oocytes undergo meiotic arrest and remain in that state until an individual’s puberty long after birth. The question is this- how does the oocyte maintain necessary active metabolism while preventing cell damage? Cells produce energy in the mitochondria through the electron transport chain coupled with oxidative phosphorylation leading to ATP that drives the metabolic machinery. However, in the course of this reactive oxygen species (ROS) are produced. While reactive oxygen species are involved in cell signaling, too much production will lead to DNA damage and mutation as well as cytotoxic effects. This damage due to reactive oxygen species is known as oxidative stress. Obviously, this is not a good result for cells that need to remain dormant for a long time. So, the question is, how does the oocyte manage a delicate balance between the necessary energy generation for low metabolism necessary for life and avoidance of high levels of reactive oxygen species?
A recent and very important study in Nature (1) provides insight into how this delicate balance occurs. Rodriquez-Nuevo and colleagues along with Elvan Böke from the Barcelona Institute of Science and Technology report their findings from a series of very careful technical studies using frog (xenopus) and human early oocytes. The frog is a good model for these studies as these vertebrates have oocyte development that is similar to that of humans. They found that the mitochondria in these early oocytes have lower membrane potential and undetectable reactive oxygen species compared to surrounding granulosa cells. In further studies these scientists found that Complex I subunits of the electron transport chain are depleted in early oocytes in both human cells and in frog cells. This complex is one of the main generators of reactive oxygen species in cells. They then conducted additional experiments using proteomic and biochemical approaches showing that early oocytes have such a low Complex I level that reactive oxygen species cannot be completely assembled. However, in these cells oxidative phosphorylation continues to support the synthesis of essential amino acids, nucleotides and heme.
This study is important and highly significant as it provides the first evidence that oocytes maintain low reactive oxygen species production while maintaining the metabolic activity necessary for longevity. This finding will help physicians treating infertility and in treating young persons with cancer who wish to preserve their fertility after cytotoxic cancer therapy.
- Rodriquez-Nuevo A, Torres-Sanchez A, Duran JM, De Guirior C, Martinez-Zamora MA, Böke E,Ooctyes maintain ROS-free mitochondrial metabolism by suppressing complex I. Nature. 2022:607: 756-761 and published supplemental material.