Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD
Authors/Creators
- 1. Max Perutz Labs, Vienna Biocenter Campus (VBC), Dr.-Bohr-Gasse 9 / Vienna Biocenter 5, 1030, Vienna, Austria
- 2. University of Vienna, Max Perutz Labs, Department of Biochemistry and Cell Biology, Dr.-Bohr-Gasse 9 / Vienna Biocenter 5, 1030, Vienna, Austria
- 3. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- 4. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia
- 5. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
- 6. Max Perutz Labs BioOptics FACS Facility, Max Perutz Labs, University of Vienna, Vienna BioCenter Campus (VBC), Vienna, Austria
- 7. Present address: Harry Perkins Institute of Medical Research, QEII Medical Centre, The University of Western Australia, Nedlands, Western Australia, Australia
- 8. Present address: Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, Nedlands, Western Australia, Australia
Description
Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PINK1/Parkin-dependent mitophagy and other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 adaptors NAP1 and SINTBAD restrict the initiation of OPTN-driven mitophagy by competing with OPTN for TBK1. Conversely, they promote the progression of NDP52-driven mitophagy by recruiting TBK1 to NDP52 and stabilizing its interaction with FIP200. Notably, OPTN emerges as the primary recruiter of TBK1 during mitophagy initiation, which in return boosts NDP52-mediated mitophagy. Our results thus define NAP1 and SINTBAD as cargo receptor rheostats, elevating the threshold for mitophagy initiation by OPTN while promoting the progression of the pathway once set in motion by supporting NDP52. These findings shed light on the cellular strategy to prevent pathway hyperactivity while still ensuring efficient progression.
Files
Figure 1.zip
Files
(770.4 MB)
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Additional details
Funding
- Aligning Science Across Parkinson's
- Mechanisms of mitochondrial damage control by PINK1 and Parkin ASAP-000350