Mitophagy · In vitro reconstitution of the initiation of mitophagosome formation
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2022-06-01 → 2024-05-31
- EU contribution
- €199,441
- Participants
- 1
- Scheme
- HORIZON-TMA-MSCA-PF-EF
Lines connect the coordinator with its partners.
Results in brief
In vitro reconstitution of the initiation of mitophagosome formation
Mitochondrial quality control is essential for cellular health, as it selectively targets damaged mitochondria for degradation through a process known as mitophagy. The primary regulatory mechanisms for PINK1/Parkin-dependent mitophagy, including the prevention of overactivation and ensuring swift progression, are not fully understood. Our research focuses on elucidating the roles of TBK1 adaptors, NAP1 and SINTBAD, in regulating mitophagy. To address this, we combined a bottom-up biochemical reconstitution approach with cellular genome engineering to characterise individual steps in presence/absence of NAP1 and SINTBAD. The project's objectives were therefore following: (i) Determine how NAP1 and SINTBAD modulate the initiation and progression of mitophagy. (ii) Understand the competitive dynamics between NAP1/SINTBAD and OPTN in TBK1 recruitment. (iii) Investigate the supportive role of NAP1/SINTBAD in NDP52-mediated mitophagy. By addressing these objectives, the project aims to provide insights into cellular strategies that balance mitophagy activation and progression, preventing pathway hyperactivity while ensuring efficient clearance of damaged mitochondria. This understanding could have significant implications for diseases associated with mitochondrial dysfunction, such as neurodegenerative diseases and mitochondrial encephalopathies.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- UNIVERSITAT WIEN · WienCoordinatorAustria
Links
- View on CORDIS
- DOI: 10.3030/101062916
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e50c65b90d&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5fbd1cabf&appId=PPGMS
Data: CORDIS, © European Union