Abstract
Mutations of the PARK2 and PINK1 genes, encoding the cytosolic E3 ubiquitin-protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, respectively, cause autosomal recessive early-onset Parkinson’s disease (PD). Parkin and PINK1 cooperate in a biochemical mitochondrial quality control pathway regulating mitochondrial morphology, dynamics and clearance. This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-β hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate. Parkin overproduction in cells increased mitochondrial HSD17B10 abundance by a mechanism involving ubiquitin chain extension, whereas PARK2 downregulation or deficiency caused mitochondrial HSD17B10 depletion in cells and mice. HSD17B10 levels were also found to be low in the brains of PD patients with PARK2 mutations. Confocal and Förster resonance energy transfer (FRET) microscopy revealed that HSD17B10 recruited Parkin to the translocase of the outer membrane (TOM), close to PINK1, both in functional mitochondria and after the collapse of mitochondrial membrane potential (ΔΨm). PD-causing PARK2 mutations impaired interaction with HSD17B10 and the HSD17B10-dependent mitochondrial translocation of Parkin. HSD17B10 overproduction promoted mitochondrial elongation and mitigated CCCP-induced mitochondrial degradation independently of enzymatic activity. These effects were abolished by overproduction of the fission-promiting dynamin-related protein 1 (Drp1). By contrast, siRNA-mediated HSD17B10 silencing enhanced mitochondrial fission and mitophagy. These findings suggest that the maintenance of appropriate mitochondrial HSD17B10 levels is one of the mechanisms by which Parkin preserves mitochondrial quality. The loss of this protective mechanism may contribute to mitochondrial dysfunction and neuronal degeneration in autosomal recessive PD.
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Abbreviations
- APEX:
-
pea L-ascorbate peroxidase (K14D, W41F, E112K) variant
- CCCP:
-
carbonyl cyanide m-chlorophenylhydrazone
- ΔΨm:
-
mitochondrial membrane potential
- DAB:
-
diaminobenzidine
- DLST:
-
dihydrolipoamide S-succinyl transferase
- Dox:
-
doxycycline
- Drp1:
-
Dynamin-related protein 1
- FRET:
-
Förster’s resonance energy transfer
- HSD17B10:
-
17-β hydroxysteroid dehydrogenase type 10
- OMM:
-
outer mitochondrial membrane
- MM:
-
mitochondrial membrane
- PINK1:
-
PTEN-induced putative kinase 1
- PMPCB:
-
mitochondrial processing peptidase subunit B
- TOM:
-
translocase of the outer membrane
- VDAC1:
-
voltage-dependent anion channel 1
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Acknowledgements
We thank M Rojo and A Lombès for helpful discussions, S Jacquier for technical assistance, the Plate-Forme d’Imagerie Cellulaire de la Pitié-Salpêtrière (PICPS), G Kroemer Y, Z Ronai, Y Yarden, M Rojo, J Zschocke for providing vectors, and the Queen Square Brain Bank (QSBB, Institute of Neurology, London) for providing human brain tissue. This work was supported by Institut national de la santé et de la recherche médicale, Association France Parkinson, Fondation de France (Engt 2007 006456, Engt 2012 00034508), Agence Nationale de la Recherche (ANR-08-MNPS-02-01) APOPIS (funded by the EU under the Sixth Framework Programme, Grant Agreement LSHM-CT-2003-503330), MEFOPA (funded by the EU under the 7th Framework Programme, Grant Agreement HEALTH-2009-241791), Fondation ICM, ‘Investissements d’avenir’ ANR-10-IAIHU-06. GB and MJ were supported by a fellowship from the French Ministry of Higher Education and Research. GB was also supported by Fondation de France.
Author Contributions
GB and MJ designed, performed and analyzed the experiments and wrote the manuscript; ST designed, performed and analyzed the experiments; RF-M, HA-O, TSG and M-PM performed and analyzed the experiments; HT and AJL provided neuropathologically characterized human brain tissue; FC, CG and DG designed and provided APEX constructs and advice; KG and EAF performed the experiments, shared protocols and provided advice; AB jointly supervised the work and provided funding; OC supervised and coordinated the work, provided funding and wrote the manuscript.
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Bertolin, G., Jacoupy, M., Traver, S. et al. Parkin maintains mitochondrial levels of the protective Parkinson’s disease-related enzyme 17-β hydroxysteroid dehydrogenase type 10. Cell Death Differ 22, 1563–1576 (2015). https://doi.org/10.1038/cdd.2014.224
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DOI: https://doi.org/10.1038/cdd.2014.224
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