Autophagy is essentially the 'rubbish collection' of our cells. If there are problems in this process, which is so important for our health, diseases such as Parkinson's can result. In their latest study, leading cell biologists at the Max Perutz Labs at the University of Vienna investigated mitophagy – a form of autophagy – and came to a remarkable conclusion: the researchers have described a new trigger for mitophagy. This discovery has led to a reassessment of the hierarchy of factors that trigger autophagy. The newly discovered signalling pathways could also open up novel therapeutic options. The study has been published in the renowned journal Nature Cell Biology.

Autophagy is a self-cleaning process of the cell and is crucial for cell health in the human body. A sophisticated molecular surveillance command identifies suspicious substances – broken cell components, clumped proteins or even pathogens – and initiates their removal. Finally, defective cell components are broken down and recycled. Mitophagy is a form of autophagy in which mitochondria within a cell are specifically degraded. Dysregulation of mitophagy is particularly associated with Parkinson's disease. A better understanding of this process is therefore important for combating Parkinson's.

In a new study led by postdoctoral researcher Elias Adriaenssens from Sascha Martens' group at the Max Perutz Labs at the University of Vienna, the scientists reveal a new mechanism for triggering mitophagy. Until now, research has focused heavily on the 'PINK1/Parkin signalling pathway'. Signalling pathways are used to transmit information within cells. These complex networks of molecules control critical cellular functions such as growth, division, cell death and, indeed, mitophagy.

"When we looked at the big picture, it became clear that, apart from the much-studied 'PINK1/Parkin pathway', there were huge gaps in our knowledge of other mitophagy pathways," explains study leader Elias Adriaenssens. "Our laboratory has explored these neglected areas by using biochemical reconstitutions to gain fundamental mechanistic insights."

Newly discovered pathways are no exception

"We found that NIX and BNIP3 – two known mitophagy receptors – can trigger autophagy without binding to FIP200 (a protein), which was quite unexpected," explains Adriaenssens. FIP200 is considered essential for triggering autophagy. "This presented us with a puzzle. Despite extensive testing, we were unable to detect any interaction between FIP200 and either of the two receptors – which raises the crucial question of how they function without this supposedly crucial component," he adds. However, mass spectrometry revealed that other autophagy components, known as WIPI proteins, bind to these mitochondrial receptors. Since WIPI proteins were previously thought to act later in the signalling pathway, their involvement in triggering autophagy was surprising. Follow-up experiments confirmed these interactions and suggested that WIPI-mediated recruitment is not an exception, but may mediate previously unknown pathways in selective autophagy.

"This is an exciting discovery – it reveals a parallel trigger for selective autophagy. Instead of a single, universal mechanism, cells appear to use different molecular strategies depending on the receptor and context. Until now, no one has considered WIPI proteins to be key players in triggering autophagosome formation, but our discovery could change that view," explains Adriaenssens.

Potential for new therapies for Parkinson's disease

Looking ahead, the study raises an important question: How do cells decide between alternative mitophagy signalling pathways – why do some receptors use one and others the other, and what factors determine which pathway is used? Distinguishing between selective mitophagy signalling pathways could pave the way for therapies that specifically activate one pathway to compensate for defects in the other, which has long-term potential for the treatment of Parkinson's disease.

Original publication in Nature Cell Biology: https://www.nature.com/articles/s41556-025-01712-y

More information and Video in the press room: https://www.univie.ac.at/en/news/detail/which-signalling-pathways-in-the-cell-lead-to-possible-therapies-for-parkinsons-disease/