Project Details
Projekt
Dissecting the mechanisms linking proteasome function to mitochondrial proteostasis
Subject Area
Cell Biology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 541647076
Mitochondrial function relies on proper import of numerous proteins from the cytosol, which wires mitochondrial protein quality control to cellular proteostasis. However, the role of the ubiquitin proteasome system for mitochondrial proteostasis in mammalian cells is less well defined. The project MITOGRADE tackles the unresolved questions how mammalian mitochondrial proteostasis is governed by proteasomal protein quality control and how sensing of proteasome impairment may impact mitochondrial function. We will define molecular mechanisms linking proteasome function to mitochondrial protein import, determine stress responses upon proteasome-dependent impairment of mitochondrial protein import and identify transcriptional regulators of proteasomopathy-linked mitochondrial dysfunction. To address these aims, we will take advantage of an interdisciplinary cross-species approach investigating conserved mechanisms in C. elegans combined with the knowledge acquired from human cells of proteasomopathy patients harboring inborn errors of the proteasome. Our collaborative project will include the establishment of novel proteasomopathy models in C. elegans, CRISPR/Cas-engineered surrogate cell lines, primary T cells from patients and induced pluripotent stem cell (iPSC)-derived glia and organoids. We will elucidate how proteasomal protein quality control is integrated into the cellular proteostasis network, alters mitochondrial protein import, and leads to metabolic and inflammatory stress responses. Our project will provide molecular insight into the general biology of proteostasis and mitochondrial function, the integration of mitochondria into the cellular proteostasis network, while also revealing pathomechanisms of specific proteasome-linked mutations in humans.
DFG Programme
Priority Programmes
