In vitro reconstitution of the initiation of mitophagosome formation

Mitophagy is a tightly controlled process in which dysfunctional mitochondria are isolated and selectively degraded by autophagy. Many cell types critically rely on this pathway and mitophagy is therefore essential to life. For instance, egg fertilization or red blood cell development would not be possible without mitophagy.

The importance of mitophagy is further underscored by its many links to human disease, most evident by mutations in the protein kinase PINK1 and the E3 ubiquitin ligase Parkin, causing autosomal recessive Parkinson’s disease.

While most factors required for mitophagy are known, a major outstanding question is: how do the different factors come together to produce a mitophagosome?

As the process comprises many different factors, each with a unique role, this is a challenging scientific question to address.

The goal of this project is to gain insight into this process, using biochemical reconstitution, to elucidate how more than 15 different factors work together to initiate the formation of a mitophagosome.

A unique aspect about our approach is that it not only allows to elucidate how mitophagosome formation is initiated, it could also reveal additional layers of fine-tuning, for instance also explaining how mitophagy is prevented from being initiated too early.

This project may therefore lead to a major step forward, establishing a coherent framework of how mitophagosome formation is organized. Moreover, it could lead to new avenues for treating devastating neurodegenerative diseases like Parkinson.