Project Details
Projekt
MFN2 role, origin and evolution in protein aggregation and mitochondrial import capacity
Subject Area
Biochemistry
Cell Biology
Cell Biology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 541758846
Mitochondria are important organelles, in health and disease, whose function goes much beyond providing energy in the form of ATP. They are plastic double-membrane structures that can remodel their own shape, proteome composition and metabolic state. This plasticity empowers mitochondria to quickly respond to both internal and external cues. In addition, their functional condition dictates cellular proteostasis, which also depends on cellular chaperones and on the ubiquitin proteasome system. However, little is known about molecular gatekeepers involved. Mitofusins, the proteins responsible for mitochondrial fusion, can sense and respond to many different stimuli through their ubiquitylation. We recently reported on a ubiquitin-dependent proteolytic stress response, at the mitochondrial surface. It allows converging these many different signals into a common cellular response, which modulates mitochondrial functionality. Not surprisingly, mutations and decreased levels of the mitofusin MFN2 are linked to a big range of diseases, mainly comprising neuronal pathologies and metabolic disorders. Nevertheless, the disease-relevant molecular mechanisms are not known. Interestingly, beyond membrane remodelling, additional roles of MFN2 were recently identified, expanding the possibilities to explore its involvement in cellular homeostasis or disease. For example, we found that MFN2 ablation impairs protein import into mitochondria and causes pronounced proteostasis defects, leading to the accumulation of protein aggregates on the cytoplasmic side. While being very surprising, this finding offers unprecedented perspectives to overarchingly understand the cellular proteome required to maintain homeostasis. In this project, we propose to elucidate the quality control roles of MFN2, using a combination of biochemical, bioinformatical and microscopical methods. We wish to define how MFN2 regulates protein import and how it prevents protein aggregation. Importantly, we already connected MFN2 to the ubiquitin-proteasome system and to a subset of cytosolic chaperones. Therefore, to precisely determine how this proteostasis network contributes to the gatekeeper properties of MFN2, we will define their relevant cellular location and interactome. Taken together, our project will uncover the molecular mechanisms allowing MFN2 to ensure proper protein import into mitochondria, but will also dissect how cytosolic quality control components cooperate with mitochondria to ensure a proper composition of the mitochondrial proteome. These two questions are at the heart of the priority program on the "Integration of mitochondria into a cellular proteostasis network".
DFG Programme
Priority Programmes
