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Evading ageing: Mitochondrial and proteostatic adaptations in oocytes

; Centre for Genomic Regulation

Female germ cells, oocytes, have the remarkable ability to survive for long periods of time, up to 50 years in humans, while retaining the ability to give rise to a new organism. We know surprisingly little about the molecular mechanisms through which oocytes alleviate cellular ageing, and why such mechanisms eventually fail with advanced age. My lab studies longevity mechanisms and their regulation in dormant oocytes. Here, I will talk about two of our recent discoveries that could partially explain the remarkable longevity of oocytes: - We have revealed oocyte dormancy involves mitochondrial activity without generation of Reactive Oxygen Species (ROS). We discovered that vertebrate (frog and human) oocytes dispense with mitochondrial complex I, one of the major ROS generators in the cell, while keeping the rest of the oxidative phosphorylation system active. This dramatic modulation of mitochondrial architecture enables low mitochondrial activity to keep mitochondria polarized to support production of essential biomolecules while avoiding ROS (Rodríguez-Nuevo et al, Nature, 2022). - We discover that, surprisingly, mouse oocytes accumulate protein aggregates even in young, healthy individuals. These aggregates are sequestered within specialised compartments that we named EndoLysosomal Vesicular Assemblies (ELVAs). ELVAs are non-membrane-bound compartments composed of endolysosomes, autophagosomes and proteasomes. We found that ELVAs do not have degradative activity in early, immature oocytes and sequester aggregated proteins during oocyte growth. ELVAs gain degradative capacity at the final stages of oocyte growth, and degrade protein aggregates. Thus, ELVAs ensure the passage of an aggregate-free cytoplasm to the early embryo while optimising for resources in the oocyte and the early embryo (Zaffagnini et al., in revision).

One of the biggest problems developed nations face is late-motherhood and associated fertility problems due to ageing oocytes. More than 25% of female fertility problems are unexplained, pointing to a huge gap in our understanding of female reproduction. Elvan’s lab strives to help fill this gap by studying the molecular mechanisms through which oocytes evade ageing for decades, and why these strategies eventually fail with advanced maternal age. Elvan completed her undergraduate degree in Molecular Biology and Genetics in her native Turkey in 2008. She received her postgraduate training in the UK (PhD in biomedicine at the CRUK-Manchester Institute) and in Boston, USA (postdoc in the department of Systems Biology at Harvard Medical School). She started her laboratory “Oocyte Biology and Cellular Dormancy” at CRG in 2017. Elvan received several international and national honours, including the European 51���� Council Starting Grant in 2017, the Consolidator Grant in 2022 and an EMBO Young Investigator Award in 2021.