Project Details
Projekt
The role of J-domain proteins in quality control of mitochondrial protein import
Subject Area
Biochemistry
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 541555098
Mitochondria import about 1000 different proteins that are produced as precursors on cytosolic ribosomes. Cytosolic chaperones like Hsp70 and their co-chaperones, the J-domain proteins, guide precursor proteins to the mitochondrial surface. The translocase of the outer membrane (TOM complex) imports most of these precursor proteins in a largely unfolded state into mitochondria. Premature folding of the precursor proteins, decreased membrane potential or damage of the translocon can cause stalling of precursor proteins in the translocation channel. Consequently, non-imported precursor proteins accumulate in the cell that in turn induce a cellular stress response and eventually cell death. Molecular mechanisms exist that clears precursor proteins from the TOM complex. The mitochondrial protein translocation-associated degradation (mitoTAD) removes translocation-stalled precursor proteins from the TOM channel under constitutive conditions, while the mitochondrial compromised protein import response (mitoCPR) clears the TOM complex upon import stress conditions. Whether cytosolic chaperones function in the removal of non-imported precursor proteins remains unknown. Our preliminary data indicate that cytosolic J-domain proteins are involved in the quality control of non-imported precursor proteins. In this project, we aim to combine the advantages of baker´s yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans to define the molecular functions and physiological role of J-domain proteins in monitoring mitochondrial protein import. First, we aim to identify the cytosolic J-proteins that are required for the clearance of mitochondrial precursor proteins. Using a combination of in vivo and in vitro assays, we will define the function of the individual J-domain proteins for degradation, extraction from translocon and ubiquitylation of mitochondrial precursor proteins. Second, we will analyse the role of J-domain proteins in the cellular distribution of non-imported mitochondrial precursor proteins, including their sequestration and disassembly in transient protein depositis. Third, we will investigate in C. elegans the role of J-domain proteins during protein import stress for activation of cellular stress responses such as the mitochondrial unfolded protein response (UPRmt), integrated stress response (ISR) and heat shock response (HSR). We will study the physiological relevance of J-domain protein-mediated quality control on the cellular as well as organismal level in C. elegans. Furthermore, we will assess the role of J-domain protein-mediated protein quality control for the function of high energy demanding neuronal and muscle tissues of the nematode. Altogether, the planned studies will reveal important molecular mechanisms how J-domain proteins integrate mitochondrial protein biogenesis into the cellular proteostasis network and their physiological role for neuronal and muscle function.
DFG Programme
Priority Programmes
