Program Summary

Scientific Background

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.

The fate of mitochondrial precursor proteins under physiological and pathological conditions: an intricate cooperation between different cellular compartments. Quality control and regulated targeting of mitochondrial precursors starts at the ribosome and involves various molecular chaperones and co-chaperones that can also be located at the ER. Under pathological conditions when mitochondrial import is impaired due to mitochondrial depolarisation or clogging of the TOM channel, non-imported precursor proteins are degraded by the proteasome in the cytoplasm and nucleus. If the quality control components are overwhelmed, for example by proteotoxic stress caused by the presence of protein aggregates linked to neurodegenerative diseases, mitochondrial precursors eventually accumulate and aggregate. © SPP2453

Central questions of the SPP2453

How does the cross-talk between cellular compartments ensure specific protein transport to mitochondria?
How do quality control pathways across different cell organelles cooperate in the removal of non-imported mitochondrial precursor proteins?
How are proteostasis mechanisms balanced to adjust mitochondrial biogenesis to cellular requirements and what is their implication for cellular viability and organismal health?

Aims and Objectives

We will combine advanced technologies and expertise of two research fields, mitochondrial protein import and cellular proteostasis, to gain insights into the cellular processes that occur upstream of protein import into mitochondria. Tandem and tridem projects with mitochondrial scientists and proteostasis researchers will address how mitochondria are integrated into the cellular proteostasis network on different levels.

We will characterize the mechanisms of targeting and degradation of mitochondrial precursor proteins with highly innovative biochemical and biophysical techniques.
We will use novel proteomic approaches to study mislocalization and stability of non-imported mitochondrial proteins in response to cellular stress.
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.

These approaches will enable us to characterize the involved cellular processes in vitro and their physiological relevance in three defined model systems with increasing complexity (Saccharomyces cerevisiae, mammalian cells and Caenorhabditis elegans). It is anticipated that our findings will serve as a paradigm for the fundamental cell biological question how organelles are integrated into the cellular quality control network. Moreover, our findings will contribute to a better understanding of molecular mechanisms underlying aging and the development of neurodegenerative diseases that are characterized by a decline in the fidelity of cellular quality control.