aMUST · Alteration of Mfn2 protein and Endoplasmic Reticulum to Mitochondria calciUm transfer in STress
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-05-01 → 2022-08-30
- EU contribution
- €191,149
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Alteration of Mfn2 protein and Endoplasmic Reticulum to Mitochondria calciUm transfer in STress
Chronic stress has been described as a risk factor for anxiety and depression, currently affecting 25% of the population and increasing the economic burden on society (representing more than €170 billion per year in EU). In this context, this MSC action aimed to decipher the neurobiological mechanisms underlying stress response under adaptative (acute) or pathological (chronic threats) conditions. Understanding the molecular differences between these responses is crucial to address the impaired mechanism that occurs during chronic stress and reduce the impact of stress on psychopathologies. As energy demand could be involved in this process, this project has been focused on the study of mitochondria and mitochondrial-endoplasmic reticulum contact sites, as they can modulate several functions within the cell, including those that may be key to providing energy to the cell. With this porpoise the researcher had two objectives: to determine the impact of stress on mitochondrial function through Mfn2 expression, Mitochondrial Associated Membranes (MAMs) structure and function, and to test the implication of Mfn2 and MAMs in stress through a behavioural readout. This project allowed the researcher to use in vivo models and employ gold standard techniques to unveil this crucial biological question, as the use of behavioural tests to measure the impact of stress on social dominance, in vivo calcium imaging and techniques that allowed the identification of different cell types in this process. In the course of the action, the investigator was able to conclude that corticosterone correlated with the adaptative situational dominance response observed in the face of acute stress and that the effect changed as a function of the duration of stress. A different contribution of corticosterone was also observed in mitochondrial oxidative respiration in mPFC and NAc, two regions involved in stress, and depending on whether the stress was acute or chronic. Finally, corticosterone could modify MAMs in a cell-specific. The conclusions of the action shed light on the regions affected upon adaptative or pathologic stress and open new avenues to interfere with the corticosterone pathway to treat associated psychopathologies.
Data: CORDIS, © European Union
Project objective
Stress conditions threaten the organism’s homeostasis triggering adaptative responses. One of them is the increased energy demand from the brain. When stress becomes chronic, it leads to behavioural changes that range from adaptation to psychopathology. aMUST project aims to understand the neurobiological mechanisms underlying stress response. Considering that nowadays chronic stress is a risk factor for psychopathologies, such as anxiety and depression, with 25% of incidence in the population and an economical burden of €170 billion/year in EU, the aMUST project is extremely relevant and timely. Mitochondria and bioenergetics are emerging as important key players in stress-related pathologies. Whereas the energy-related impact of stress has received considerable attention in the past few years, the critical importance of the specialized cellular hubs called mitochondrial-endoplasmic reticulum (ER) associated membranes (MAMs) in stress responses, remains to be elucidated. Combining cutting-edge approaches, the aMUST project will shed light on this crucial biological question. Accordingly, intracranial lenses insertion of the mini endoscope in stress-vulnerable brain regions will be used to allow the study of in vivo mitochondrial calcium dynamics during behavioral experiments. 3D electron microscopy, protein ligase assay and BioID in vivo proteomics will allow to determine composition in MAMs structures and which protein interactions are altered during stress. The use of transgenic animals, compounds that change MAMs proteins function and alleviate ER-stress will be used to prevent possible modifications that cause vulnerability to stress. Therefore, aMUST project outcomes will unveil the MAMs-related mechanisms needed to open new therapeutic avenues to promote resilience to stress.
Original text from CORDIS.
Participants
- ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE · LausanneCoordinatorSwitzerland
Links
Data: CORDIS, © European Union