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A team of cell biologists from the Max Perutz Labs at the University of Vienna has identified a previously unrecognised pathway that activates mitophagy, a process in which damaged mitochondria are selectively degraded. The findings, published in Nature Cell Biology, indicate that mitophagy can proceed independently of the FIP200 protein, a component long believed to be essential for initiating autophagy.
Autophagy enables cells to eliminate dysfunctional components, helping maintain cellular homeostasis. In mitophagy, the target is mitochondria, the energy-generating structures in cells. Problems in this pathway have been linked to neurodegenerative conditions, including Parkinson’s disease. Most current models describe mitophagy as being initiated through the PINK1/Parkin pathway, a well-studied signalling mechanism in cellular biology.
FIP200 independence raises new questions
The new study, led by postdoctoral researcher Elias Adriaenssens in Sascha Martens’ group, focused on mitophagy receptors NIX and BNIP3. Using a series of biochemical reconstitution experiments, the researchers showed that these receptors can induce autophagy without interacting with FIP200. This was an unexpected finding, as FIP200 has been widely regarded as indispensable for autophagosome formation.
Further analysis using mass spectrometry revealed that WIPI proteins, previously thought to act downstream in the autophagy signalling cascade, interact directly with NIX and BNIP3. Follow-up experiments confirmed that these interactions can trigger autophagy, suggesting the existence of parallel pathways that bypass FIP200.
Implications for understanding disease mechanisms
The discovery that WIPI proteins may initiate mitophagy expands the known signalling architecture of autophagy and introduces additional complexity to how cells manage mitochondrial quality control. It also prompts new research questions: under what conditions do cells use one pathway over another, and how might selective modulation of these routes influence disease outcomes?
Although the study was not conducted in human patients, the identification of multiple mitophagy pathways could inform future therapeutic strategies for conditions such as Parkinson’s disease, where mitochondrial dysfunction plays a central role.
Reference: Adriaenssens E, Schaar S, Cook ASI, et al. Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery. Nat Cell Biol. 2025. doi: 10.1038/s41556-025-01712-y
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