Diverse genes associated with familial Parkinson's disease (familial Parkinsonism) have been implicated in mitochondrial quality control. One such gene, PARK7 encodes the protein DJ-1, pathogenic mutations of which trigger its translocation from the cytosol to the mitochondrial matrix. The translocation of steady-state cytosolic proteins like DJ-1 to the mitochondrial matrix by missense mutations is rare and the underlying mechanism remains to be elucidated. Here, we show that the protein unfolding associated with various DJ-1 mutations drives its import into the mitochondrial matrix. Increasing the structural stability of these DJ-1 mutants restores cytosolic localization. Mechanistically, we show that a reduction in the structural stability of DJ-1 exposes a cryptic N-terminal mitochondrial targeting signal (MTS) including Leu10 that promotes DJ-1 import into the mitochondrial matrix for subsequent degradation. Our work describes a novel cellular mechanism for targeting a destabilized cytosolic protein to the mitochondria for degradation.
Unfolding is the driving force for mitochondrial import and degradation of Parkinson's disease-related protein DJ-1
These authors contributed equally to this work
- Award Group:
- Funder(s): Japan Society for the Promotion of Science
- Award Id(s): JP18K06237
- Funder(s):
- Award Group:
- Funder(s): Japan Agency for Medical Research and Development
- Award Id(s): CREST
- Funder(s):
Currently Viewing Accepted Manuscript - Newer Version Available
- Split-screen
- Views Icon Views
- Open the PDF for in another window
-
Article Versions Icon
Versions
- Version of Record 25 November 2021
- Accepted Manuscript 22 October 2021
- Share Icon Share
-
Tools Icon
Tools
- Search Site
Bruno Barros Queliconi, Waka Kojima, Mayumi Kimura, Kenichiro Imai, Chisato Udagawa, Chie Motono, Takatsugu Hirokawa, Shinya Tashiro, Jose M.M. Caaveiro, Kouhei Tsumoto, Koji Yamano, Keiji Tanaka, Noriyuki Matsuda; Unfolding is the driving force for mitochondrial import and degradation of Parkinson's disease-related protein DJ-1. J Cell Sci 2021; jcs.258653. doi: https://doi.org/10.1242/jcs.258653
Download citation file:
Advertisement
Imaging Cell Architecture and Dynamics
We are still welcoming submissions for our upcoming Special Issue: Imaging Cell Architecture and Dynamics. This issue will be coordinated by two Guest Editors: Lucy Collinson (The Francis Crick Institute, UK) and Guillaume Jacquemet (University of Turku, Finland). Extended submission deadline: 29 March 2024.
Journal of Cell Science - more than just a journal
People who know JCS well will know that we're more than just a journal and that our community – the cell biology community – really is at the heart of everything we do. Read the full Editorial by Editor-in-Chief Michael Way and Executive Editor Seema Grewal.
2024 Journal Meeting 'Diversity and Evolution in Cell Biology'
Registration is open for our 2024 Journal Meeting Diversity and Evolution in Cell Biology, which aims to bring together evolutionary biologists and cell biologists investigating diverse aspects of cellular physiology. Submit your abstract by 5 April. Final registration deadline: 3 May 2024.
Workshop: Roles of Lipids in Nuclear Homeostasis and Genome Stability
Early-career researchers interested in the roles of nuclear lipids, apply now for one of the ten funded places at this Workshop, which will take place 14-17 October 2024. Application deadline: 19 April.
Reasons to submit to Journal of Cell Science
There are many benefits to publishing in Journal of Cell Science - read more about why you should choose JCS or visit our submission page now.