SPP 2453:  Integration of mitochondria into the cellular proteostasis network

• Subject Area: Biology ; Medicine
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521173510

Mitochondrial biogenesis and functions depend on the import of more than 1000 proteins that are produced as precursors on cytosolic ribosomes. Although defects in mitochondrial function play a critical role in aging and neurodegenerative diseases, mechanisms and quality control of precursor protein targeting to mitochondria are poorly characterized. Protein import into mitochondria occurs predominantly post-translationally so that precursor proteins transiently accumulate in the cytosol. Recent studies showed that these precursor proteins are a severe burden to cellular proteostasis. They occupy and challenge the cytosolic quality control system. Particularly in aging cells, when mitochondrial functionality decreases, the accumulation of precursors represents a threat to cellular proteostasis, thereby linking mitochondrial fitness to cellular health. Vice versa, a decline in the proteostasis network capacity favours the accumulation of non-imported precursors. Despite its high relevance, the mechanisms that govern mitochondrial protein biogenesis and their crosstalk to proteostasis components have remained largely unknown. In this priority program, researchers from different scientific backgrounds will address in an interdisciplinary approach central questions in the emerging field of cellular quality control of mitochondrial precursor proteins. (i) How does the cross-talk between cellular compartments ensure specific protein transport to mitochondria? (ii) How do quality control pathways across different cell organelles cooperate in the removal of non-imported mitochondrial precursor proteins? (iii) How are proteostasis mechanisms balanced to adjust mitochondrial biogenesis to cellular requirements and what is their implication for cellular viability and organismal health? We will combine advanced technologies and expertise of two research fields, mitochondrialprotein import and cellular proteostasis, to gain insights into the cellular processes that occur upstream of protein import into mitochondria. Tandem projects with one mitochondrial scientist and one proteostasis researcher will address how mitochondria are integrated into the cellular proteostasis network on different levels. First, we will characterize the mechanisms of targeting and degradation of mitochondrial precursor proteins with highly innovative biochemical and biophysical techniques. Second, we will use novel proteomic approaches to study mislocalization and stability of non-imported mitochondrial proteins in response to cellular stress. Finally, we will use super-resolution microscopic technologies to follow the fate of non-imported proteins in single cells and to investigate the role of organellar cooperation in sorting and degradation of mitochondrial proteins.

• DFG Programme: Priority Programmes

Projects

• Causes, consequences and correction of mitochondrial protein misfolding (Applicants Hartl, Franz-Ulrich ;  Jae, Ph.D., Lucas )
• Contributions of ubiquitin signaling to the maintenance of mitochondrial import channels (Applicants Methner, Axel ;  Ulrich, Ph.D., Helle )
• Coordination Funds (Applicant Becker, Thomas )
• Coordination of proteostasis and mitochondrial intermembrane space protein import (Applicants Hoppe, Thorsten ;  Riemer, Jan )
• Dissecting the mechanisms linking proteasome function to mitochondrial proteostasis (Applicants Bano, Daniele ;  Bartelt, Alexander ;  Krüger, Elke Beate )
• Early steps in the biogenesis of mitochondrial inner membrane proteins: The role of cytosolic factors in synthesis, targeting and quality control (Applicants Herrmann, Johannes M. ;  Pfeffer, Stefan ;  Winklhofer, Konstanze )
• In vivo profiling of authentic cytosolic targeting routes of mitochondrial precursor proteins (Applicants Kramer, Günter ;  Vögtle, Friederike-Nora )
• Interplay between local translation of mitochondrial proteins and proteostasis in neurons (Applicants Dudanova, Ph.D., Irina ;  Harbauer, Angelika )
• Mechanisms of mitochondrial proximal translation and co-translational protein import (Applicants Bykov, Yury ;  Mattei, Simone )
• MFN2 role, origin and evolution in protein aggregation and mitochondrial import capacity (Applicants Escobar-Henriques, Mafalda ;  Hofmann, Kay )
• Nuclear quality control of non-imported mitochondrial precursor proteins (Applicants den Brave, Fabian ;  Mogk, Axel )
• Regulation of the human proteostasis network under mitochondrial protein import stress (Applicants Dennerlein, Ph.D., Sven ;  Meiners, Silke ;  Warscheid, Bettina )
• The contribution of cytosolic chaperones to the biogenesis of mitochondrial proteins (Applicants Buchner, Johannes ;  Rapaport, Doron )
• The role of cotranslational protein biogenesis factors in the translation and targeting of mitochondrial precursor proteins (Applicants Deuerling, Elke ;  Münch, Christian )
• The role of J-domain proteins in quality control of mitochondrial protein import (Applicants Becker, Thomas ;  Kirstein, Janine )
• The role of lysosomal protein degradation in mitochondrial membrane stress responses (Applicants van der Laan, Martin ;  Winter, Dominic )

• Spokesperson: Professor Dr. Thomas Becker