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Sci Rep. 2019 Aug 14;9(1):11829. doi: 10.1038/s41598-019-47352-9.

The PINK1 kinase-driven ubiquitin ligase Parkin promotes mitochondrial protein import through the presequence pathway in living cells.

Jacoupy M1,2,3,4, Hamon-Keromen E1,2,3,4, Ordureau A5, Erpapazoglou Z1,2,3,4, Coge F4,6,7, Corvol JC1,2,3,4,8, Nosjean O7, Mannoury la Cour C7, Millan MJ7, Boutin JA7, Harper JW5, Brice A1,2,3,4, Guedin D4,6,7, Gautier CA9,10,11, Corti O12,13,14,15.

Author information

1
Inserm, U1127, F-75013, Paris, France.
2
CNRS, UMR 7225, F-75013, Paris, France.
3
Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.
4
Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
5
Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
6
Laboratoire de Chémogénétique Servier, F-75013, Paris, France.
7
Institut de Recherches Servier, Croissy-sur-Seine, France.
8
Assistance-Publique Hôpitaux de Paris, Inserm, CIC-1422, Department of Neurology, Hôpital Pitié-Salpêtrière, F-75013, Paris, France.
9
Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France. clement.gautier@servier.com.
10
Laboratoire de Chémogénétique Servier, F-75013, Paris, France. clement.gautier@servier.com.
11
Institut de Recherches Servier, Croissy-sur-Seine, France. clement.gautier@servier.com.
12
Inserm, U1127, F-75013, Paris, France. olga.corti@upmc.fr.
13
CNRS, UMR 7225, F-75013, Paris, France. olga.corti@upmc.fr.
14
Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France. olga.corti@upmc.fr.
15
Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France. olga.corti@upmc.fr.

Abstract

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.

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