Mitochondrial Precursor Proteins in the Cytosol as Major Determinants of Cellular Health

Introduction

Mitochondria are made of 800 to 1500 proteins which represent up to 30% of the cellular mass. Owing to their post-translational mode of import, mitochondrial precursor proteins explore the cytosol before they are imported into mitochondria. These reactions are of utmost importance for cellular functionality since cytosolic precursors pose a major threat to cellular proteostasis and are major drivers in aging and for the pathogenesis of neurodegenerative diseases. Still, the biology of cytosolic precursors is largely elusive.

Research Context

In vitro import assays governed the experimentation platform of the mitochondrial community, which enabled exquisite breakthroughs in understanding translocation. However, these assays are unsuited to elucidate cytosolic reactions.

Project Goals

MitoCyto aims to break out of these experimental walls to elucidate the biology of cytosolic precursors. This will be achieved with an interdisciplinary research team that leaves the comfort zone of biochemistry to utilize genetic and cell biology approaches. The team will also develop novel cutting-edge techniques, including:

1. High throughput approaches
2. Microfluidics-assisted microscopy
3. Synthetic biology

Research Questions

From this innovative combination, detailed mechanistic insights into three so far largely elusive aspects of cell biology will be possible for the first time:

1. What are the cytosolic interactors of mitochondrial precursor proteins?
2. What are the direct and indirect physiological consequences of cytosolic precursor accumulation?
3. How does the re-routing of mitochondrial proteins to the nucleus control growth and fitness of eukaryotic cells?

Conclusion

We are convinced that MitoCyto will break ground towards a comprehensive understanding of how eukaryotic cells maintain a healthy proteome over a lifetime despite fluctuating metabolic conditions. While these goals are conceptually deeply rooted in a comprehensive understanding of basic biological questions, they are of immediate relevance for cancer cell metabolism, neurodegeneration, and aging.