Project description
Cellular fitness maintenance in dormant oocytes
Female germ cells, oocytes, can survive for long periods while retaining the ability to create a new organism. The molecular mechanisms that allow oocytes to evade cellular ageing are poorly understood. The ERC-funded ACTIVEDORMANCY project aims to uncover the mechanisms behind the maintenance of cellular fitness and how these mechanisms are affected by ageing, employing imaging and state-of-the-art omics technologies. Oocyte dormancy involves at least two recently discovered unique mechanisms: the suppression of mitochondrial complex I and the constitutive activation of mitochondrial unfolded protein response. The current project will study the metabolic adaptations of cell survival without mitochondrial complex I, the long-lived oocyte proteins and their regulation, and the quality control mechanisms in dormant oocytes.
Objective
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.
The goal of this research proposal is to reveal both the mechanisms dormant oocytes employ to maintain cellular fitness and how ageing affects these mechanisms, combining biochemical perturbations with imaging and state-of-the-art -omics techniques. We have recently discovered that oocyte dormancy involves two mechanisms not reported in any animal cell type before: the suppression of mitochondrial complex I, and the constitutive activation of mitochondrial unfolded protein response. These discoveries point to a set of poorly understood strategies that oocytes use to minimise damage to their cellular components during their long lifespan. In this project, we focus on three new interlinked directions to reveal mechanisms that dormant oocytes employ to keep a ‘youthful’ cytoplasm: 1) Characterise the metabolic adaptations that enable life without mitochondrial complex I 2) Study extremely long-lived oocyte proteins and their regulation 3) Identify and characterise the quality control mechanisms that eventually fail in dormant oocytes to impact fertility. We will use oocytes from frogs, mice, and humans which are complementary in their ease of handling and relevance to human physiology.
One of the biggest problems developed nations face is late-motherhood and associated fertility problems due to ageing oocytes. >25% of female fertility problems are unexplained, pointing to a huge gap in our understanding of female reproduction. This proposal will help fill this gap by studying longevity mechanisms in dormant oocytes. It will further provide insights into the metabolic adaptations of long-lived cells, female fertility, and ageing.
Fields of science
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
08003 Barcelona
Spain