Project Details
Projekt
The role of lysosomal protein degradation in mitochondrial membrane stress responses
Applicants
Professor Dr. Martin van der Laan; Dr. Dominic Winter
Subject Area
Biochemistry
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 541758477
Mitochondria play critical roles in cellular metabolism and bioenergetics, serve as main suppliers of ATP, and host diverse anabolic and catabolic pathways. Contemporary studies place mitochondria at the center stage of intracellular signaling pathways and attribute to them roles in determining cell fate decisions. However, little is known how they integrate into global cellular stress responses and how mitochondrial quality control systems cooperate with other subcellular compartments to sustain cellular homeostasis. Mitochondrial dysfunction can result in apoptosis, if major malfunctions are not corrected, e.g. by selective removal of mitochondrial network portions through autophagy. To date, few specific adaptive pathways were identified that are triggered by proteostatic threats, including mitochondrial protein import block or accumulation of mistargeted proteins. In contrast to previous assumptions, mitochondrial membrane systems are also connected to the endo-lysosomal system through formation of hitherto ill-defined vesicular structures, termed mitochondria-derived vesicles (MDVs). As a matter of fact, this exciting quality control pathway, which enables removal of fully assembled membrane protein complexes, is alarmingly understudied. It is, for example, completely unknown what defines their content, how MDVs contribute to the mitochondrial stress response, and if lysosomal degradation is indeed their ultimate fate. With this project, we start the first comprehensive interdisciplinary approach to address these important questions. We will utilize genome-edited mammalian cell lines to study the consequences of mitochondrial stress, like membrane deformation or altered protein assembly and phospholipid composition, on MDV formation and protein content. These conditions will be complemented by the use of chemical inhibitors of lysosomal or mitochondrial functions, to discern the effect of distinct pathways on MDV biogenesis and fate. We will use a combination of mass spectrometry-based proteomics, bioinformatics, high-resolution imaging, biochemical protein complex analysis, and metabolic measurements to unravel the contribution of MDVs to mitochondrial homeostasis and global cellular stress response programs.
DFG Programme
Priority Programmes
