PD-MitoQUANT partners at Institut du Cerveau et de la Moelle Epinière recently co-authored a study entitled “The PINK1 kinase-driven ubiquitin ligase Parkin promotes mitochondrial protein import through the presequence pathway in living cells.” in Scientific Reports on August 14, 2019. This work was undertaken by M. Jacoupy, E. Hamon-Keromen, A.Ordureau, Z. Erpapazoglou, F. Coge, J.-C. Corvol, O. Nosjean, C. Mannoury laCour, M. J. Millan, J.A. Boutin, J.W. Harper, A. Brice, D.Guedin, C.A.Gautier and O. Corti. Congratulations to the team!
“Most of over a thousand mitochondrial proteins are encoded by nuclear genes and must be imported from the cytosol. Little is known about the cytosolic events regulating mitochondrial protein import, partly due to the lack of appropriate tools for its assessment in living cells. We engineered an inducible biosensor for monitoring the main presequence-mediated import pathway with a quantitative, luminescence-based readout. This tool was used to explore the regulation of mitochondrial import by the PINK1 kinase-driven Parkin ubiquitin ligase, which is dysfunctional in autosomal recessive Parkinson’s disease. We show that mitochondrial import was stimulated by Parkin, but not by disease-causing Parkin variants. This effect was dependent on Parkin activation by PINK1 and accompanied by an increase in the abundance of K11 ubiquitin chains on mitochondria and by ubiquitylation of subunits of the translocase of outer mitochondrial membrane. Mitochondrial import efficiency was abnormally low in cells from patients with PINK1- and PARK2-linked Parkinson’s disease and was restored by phosphomimetic ubiquitin in cells with residual Parkin activity. Altogether, these findings uncover a role of ubiquitylation in mitochondrial import regulation and suggest that loss of this regulatory loop may underlie the pathophysiology of Parkinson’s disease, providing novel opportunities for therapeutic intervention.”
Sci Rep. 2019 Aug 14;9(1):11829. DOI: 10.1038/s41598-019-47352-9.
Download the gold open access publication here.
This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821522. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and Parkinson’s UK.
The material presented and views expressed here reflect the author’s view and neither IMI nor the European Union, EFPIA, or any Associated Partners are responsible for any use that may be made of the information contained herein.