Project Details
Projekt
The role of cotranslational protein biogenesis factors in the translation and targeting of mitochondrial precursor proteins
Subject Area
Biochemistry
Cell Biology
Cell Biology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 541647156
Cytonuclear and secretory proteins are translated in the cytosol and cotranslationally processed by various ribosome-associated factors including peptidases, transferases, chaperones and transport factors. These cotranslational factors ensure the proper maturation and transport of these proteins. In addition, most mitochondrial proteins are translated in the cytosol and imported into mitochondria. Yet, whether cotranslational processing factors are also important for mitochondrial protein biogenesis and transport remains poorly understood. In addition to aiding with the proficient import of mitochondrial proteins, cotranslational biogenesis factors would also offer a tightly-linked regulatory target to connect the mitochondrial functional status with the production of new mitochondrial proteins. Our preliminary work has provided mechanistic insight suggesting that cotranslational protein biogenesis factors are closely connected to mitochondrial protein synthesis and import. We found that the nascent polypeptide-associated complex (NAC), a cotranslational factor that directs newly synthesized proteins into proper biogenesis pathways, binds broadly to ribosomes translating mitochondrial proteins. Loss of NAC in cells lowers mitochondrial protein import efficiency suggesting a crucial cotranslational function of NAC in mitochondrial protein sorting. Upon various mitochondrial stress conditions, ranging from respiratory chain inhibition to mitochondrial proteostasis perturbation, we observed acute changes in NAC translation and import defects into mitochondria. These findings suggest that cotranslational biogenesis factors are crucial for mitochondrial protein synthesis/import and controlled by feedback loops that signal mitochondrial health. Here, we aim to investigate this hypothesis in molecular detail by addressing the following three aims:Aim 1. Investigate how mitochondrial proteins are processed by cotranslational factors and sorted into specific mitochondria protein import pathways. Aim 2. Study the role of NAC and other cotranslational factors in mitochondrial protein import. Aim 3. Identify feedback loops from mitochondrial import and proteostasis defects to cotranslational protein biogenesis factors. The planned project combines the expertise from the mitochondrial protein import field (Christian Münch) and the cellular proteostasis field (Elke Deuerling), who will work in close coordination and synergy to achieve a successful completion of the project. We will rely on a wide range of established technologies in the lab that enable this important and challenging project. By linking observed molecular mechanisms to studies in human cell models as well as in C. elegans, we will be able to provide critical insight into the role of cotranslational processing and regulation of mitochondrial proteins.
DFG Programme
Priority Programmes
