Descrizione del progetto
Errato ripiegamento delle proteine mitocondriali e ripristino della proteostasi
Molte malattie, tra cui il cancro e le malattie neurodegenerative, influenzano la funzione mitocondriale e la proteostasi, un percorso scarsamente caratterizzato nelle cellule di mammifero. In caso di errato ripiegamento proteico, per ripristinare la proteostasi i mitocondri attivano la risposta a proteine mitocondriali mal ripiegate (UPRmt, Mitochondrial Unfolded Protein Response). Il progetto mitoUPR, finanziato dall’UE, affronta la regolazione di questo percorso utilizzando strumenti per indurre l’UPRmt in cellule di mammifero combinati con spettrometria di massa quantitativa, microscopia, sequenziamento di nuova generazione ed editing genetico. Indaga inoltre sull’influenza che l’UPRmt esercita sugli ambienti dei mitocondri, del citosol e delle cellule vicine. Il progetto si propone di scoprire un nuovo strato di regolazione dello stress cellulare associato al percorso UPRmt.
Obiettivo
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.
Campo scientifico
- 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
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
60323 Frankfurt Am Main
Germania