Project description
Mitochondrial protein misfolding and the restoration of proteostasis
Many diseases, including cancer and neurodegenerative diseases, affect mitochondrial function and proteostasis, a poorly characterised pathway in mammalian cells. In the case of protein misfolding, mitochondria activate the mitochondrial unfolded protein response (UPRmt) to restore proteostasis. The EU-funded mitoUPR project addresses the regulation of this pathway using tools to induce the UPRmt in mammalian cells combined with quantitative mass spectrometry, microscopy, next-generation sequencing and gene editing. Moreover, it investigates the influence the UPRmt exerts on the environments of mitochondria, cytosol and neighboring cells. The project aims to uncover a novel layer of cellular stress regulation associated with the UPRmt pathway.
Objective
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.
Fields of science
- 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
Keywords
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Funding Scheme
ERC-STG - Starting GrantHost institution
60323 Frankfurt Am Main
Germany