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SPP 2453:  Integration der Mitochondrien in das zelluläre Proteostase-Netzwerk

Fachliche Zuordnung Biologie
Medizin
Förderung Förderung seit 2024
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 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.
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