Cell’s self-cleaning system can help fight Parkinson’s disease

The researchers found that cells can clean up damaged mitochondria using a surprising backup system that does not rely on traditional mechanical long-term ideas.

The discovery was published in Natural Cell BiologyReshaping how scientists understand the process of mitochondria, cells dealing with dysfunctional mitochondria, and can help guide new therapies for neurodegenerative diseases such as Parkinson.

Beyond the classical pathway: a new pathway to mitochondria

So far, most research on mitochondria has focused on Pink1/Parkin Pathway, where mitochondria damaged mitochondria are marked and cleared by autophagosomes. This process is believed to require FIP200, a protein scaffold that recruits the rest of the autophagy machinery.

However, this new study, led by Elias Adriaenssens and Sascha Martens of Max Perutz Labs, suggests that two mitochondrial receptors BNIP3 and NIX can bypass FIP200 completely. Instead, they recruited a group of proteins called WIPI, which was previously assumed to function only during autophagy.

Major findings from the study

• BNIP3 and NIX initiate mitochondria without binding to FIP200
• Instead, they combine WIPI2 and WIPI3, which were previously considered downstream components
• This WIPI recruitment is sufficient to trigger autophagosome formation
• WIPI – ATG13 interaction is critical for this alternative mitochondrial pathway
• Other receptors such as Tex264 and FKBP8 also use the WIPI and FIP200 pathways

A new hierarchy of autophagy components

By re-establishing the early stages of in vitro autophagy, the researchers showed that WIPI proteins can recruit and activate ULK1 complexes (usually brought by FIP200). This inversion to conventional sequences was unexpected, suggesting that WIPI proteins can be used as upstream promoters rather than pure intermediates.

“It seems to use different molecular strategies depending on the receptor and environment, rather than a single universal mechanism,” Adriaenssens said.

What’s even more surprising is that binding WIPI2 to the mitochondria surface alone is enough to initiate mitochondria, demonstrating that Wipis can start the process without any other known initiator.

This is important for Parkinson’s disease

Mitochondria are particularly important in neurons, where mitochondrial damage is associated with the development of Parkinson’s disease. While the therapy focuses on restoring PINK1/Parkin signaling, this new WIPI-mediated pathway provides another route, especially in cases where the main system is compromised.

This study opens up options for selective therapy that may amplify one pathway, which may improve cellular health in neurodegenerative diseases when the other pathway fails.

Looking to the future: A more flexible framework for autophagy

This finding also suggests that other transmembrane receptors may trigger autophagy through similar WIPI-based pathways. The team found that receptors such as Tex264 and FKBP8 involved ER-PHAGY and MITOPHAGY, respectively, also combined with WIPI2, suggesting a broader, conservative mechanism throughout the organelles.

“Under different pressures or conditions, cells may use this flexibility to fine-tune their cleaning operations,” Martens said.

Currently, this study marks a fundamental shift in our understanding of autophagosome priming. It challenges decades of assumptions and points to a more modular context-dependent model, one with exciting potential for therapeutic interventions.

Magazine

Natural Cell Biology

doi

10.1038/s41556-025-01712-y

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