Scientists have discovered that immature oocytes maintain their youth by shutting down one of the protein complexes that produce energy in mitochondria .
Live slow, stay young
Every female is endowed with a finite number of oocytes that form before birth, then reside in the ovaries in a dormant state until maturation and release. Oocytes are faced with a tricky task: they must remain in good shape throughout the body’s reproductive span in order to be able to produce healthy offspring. Interestingly, in addition to oocytes aging very slowly, early embryos undergo an enigmatic rejuvenation event so that the offspring produced by the adult organism starts from age zero .
However, as time passes, oocyte quality begins to dwindle, contributing to reproductive dysfunction, which occurs earlier than many other manifestations of aging. Researchers have been trying to understand the mechanisms involved, but with limited success. In this new groundbreaking study published in Nature, scientists from Spain made a huge leap forward, showing that oocytes modify one of the most important cellular processes so that it produces less damage.
Less energy, less byproducts
Cells acquire energy mostly via the intricate, multi-stage process known as the electron transport chain (ETC), which uses nutrients that we get from food to produce adenosine triphosphate (ATP), the ‘energy currency’ of the cell. Sadly, the system is not perfect. As professor Vadim Gladyshev (who was not involved in this study) explained in his recent interview with Lifespan.io, all biological processes produce damage as a byproduct, and the indispensable ones can produce a lot of it.
The byproducts of the ETC are the infamous reactive oxygen species (ROS). While they also do some useful work such as cellular signaling, ROS mostly just wreak havoc, inducing DNA damage and disrupting various cellular processes . Mitochondria are the main, though not the only, source of endogenous ROS.
Since ROS are linked to cellular aging , the researchers began with analyzing their levels in human and frog early-stage (immature) oocytes. Amazingly, neither produced any detectable ROS signal. The researchers then determined that the absence of ROS resulted not from their fast degradation by molecules called ROS scavengers, but from decreased ROS production. They also measured mitochondrial membrane potential which is higher when ETC is hard at work. In early-stage oocytes, membrane potential was remarkably low. Together with the low levels of mitochondrial ROS, this indicated reduced ETC activity.
Which one of the five?
The ETC is powered by five protein complexes (large molecules constructed from several different proteins), numbered from I to V. To pinpoint the particular complex that was responsible for the strange behavior of the ETC, the researchers tried shutting down the complexes one by one. Blocking any complex other than Complex I resulted in the oocytes’ death: in other words, only Complex I was not involved in any essential activity. Importantly, Complex I is also the foremost producer of ROS.
Proteomic analysis revealed that in early-stage oocytes, the levels of all ETC subunits (complex-forming proteins) were lower than in mature oocytes, with Complex I subunits almost completely absent. Somehow, oocytes managed to remodel their ETC to exclude Complex I! To date, in no other animal cell type that contains functioning mitochondria, absence of Complex I has ever been detected, and in the plant realm, the only known exception is mistletoe.
Oocytes apparently pay for this trick with diminished overall ETC activity, which is probably just enough to support immature oocytes in their dormant mode. As the researchers discovered, the ETC goes back on track – completely with Complex I – in mature oocytes that must do the heavy lifting of forming a new organism. Predictably, ROS levels also shot up in mature vs early-stage oocytes.
To sum things up, early-stage oocytes reside in a sort of hibernation: they are not really doing anything other than simply surviving, but they also accumulate very little damage. As the researchers note, stem cells, particularly neuronal and hematopoietic stem cells, also exhibit low ETC activity and ROS levels , and they are known to age slowly. The next step would be to determine whether stem cells also shut down their Complex I.
This groundbreaking study uncovers a previously unknown mechanism by which oocytes, and maybe also stem cells, greatly reduce their rate of aging. As mature organisms, we need our cells to do stuff (while accumulating damage) rather than lie dormant, so this discovery, as fascinating as it is, might not be immediately translatable into anti-aging therapies. However, it can teach us a lot about aging in general and reproductive aging in particular and, hence, about possible ways to counter it.
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 Rodríguez-Nuevo, A., Torres-Sanchez, A., Duran, J.M. et al. Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I. Nature (2022).
 Kerepesi, C., Zhang, B., Lee, S. G., Trapp, A., & Gladyshev, V. N. (2021). Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging. Science Advances, 7(26), eabg6082.
 Pizzino, G., Irrera, N., Cucinotta, M., Pallio, G., Mannino, F., Arcoraci, V., … & Bitto, A. (2017). Oxidative stress: harms and benefits for human health. Oxidative medicine and cellular longevity, 2017.
 Shields, H. J., Traa, A., & Van Raamsdonk, J. M. (2021). Beneficial and detrimental effects of reactive oxygen species on lifespan: A comprehensive review of comparative and experimental studies. Frontiers in Cell and Developmental Biology, 9, 628157.
 Khacho, M., Harris, R., & Slack, R. S. (2019). Mitochondria as central regulators of neural stem cell fate and cognitive function. Nature Reviews Neuroscience, 20(1), 34-48.
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