Description du projet
Le mauvais repliement des protéines mitochondriales et la restauration de la protéostase
De nombreuses maladies, dont le cancer et les maladies neurodégénératives, affectent la fonction mitochondriale et la protéostase, une voie mal caractérisée dans les cellules des mammifères. En cas de mauvais repliement des protéines, les mitochondries activent la réponse protéique dépliée des mitochondries (UPRmt pour «mitochondrial unfolded protein response») pour rétablir la protéostase. Le projet mitoUPR, financé par l’UE, s’intéresse à la régulation de cette voie en utilisant des outils pour induire l’UPRmt dans les cellules de mammifères, combinés à la spectrométrie de masse quantitative, à la microscopie, au séquençage de nouvelle génération et à l’édition des gènes. En outre, il étudie l’influence de l’UPRmt sur l’environnement des mitochondries, du cytosol et des cellules voisines. Le projet vise à découvrir une nouvelle couche de régulation du stress cellulaire associée à la voie de l’UPRmt.
Objectif
Mitochondrial function is central for cellular metabolism and energy balance. However, many diseases, including cancer and neurodegenerative diseases, affect mitochondrial function and proteostasis. Upon mitochondrial protein misfolding, mitochondria activate the mitochondrial unfolded protein response (UPRmt) to restore proteostasis, a poorly characterized pathway in mammalian cells. Notably, the effects of the UPRmt on its direct environment – mitochondria – and on cytosolic homeostasis remain unknown. Strikingly, non-cell autonomous signaling of metabolism and folding state has been described in recent years, particularly in worms. However, the possible role of UPRmt in such processes is undescribed.
Using newly available tools to acutely induce the UPRmt in mammalian cells, combined with cutting-edge quantitative mass spectrometry, microscopy, next generation sequencing, and gene editing approaches, we propose to address these important open questions by studying the influence UPRmt exerts on the environments of i) mitochondria (including to study the composition and regulation of RNA granules), ii) cytosol (adjustments of translation, metabolism, and proliferation) and iii) neighboring cells (modification by non-cell autonomous signaling). Additionally, we aim to develop an iPSC-based UPRmt model.
On cellular and organismal level, there ought to be mechanisms to signal changes in metabolism and proteostasis to increase robustness in neighboring environments. Studying these effects will be crucial for a better understanding of human disease and carries severe implications: i) the possibility of therapeutic treatment by modulating neighboring compartments or cells and ii) the possibility that diseases inducing the UPRmt could have unknown paracrine and endocrine effects on the organism. This proposal holds the potential to uncover a novel layer of regulation of cellular stress with an extensive influence on our understanding of the UPRmt and disease.
Champ scientifique
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein folding
- medical and health sciencesclinical medicineoncology
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
- medical and health sciencesbasic medicinephysiologyhomeostasis
Mots‑clés
Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
60323 Frankfurt Am Main
Allemagne