title: Parkin maintains mitochondrial levels of the protective Parkinson's disease-related enzyme 17-β hydroxysteroid dehydrogenase type 10.
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.
authors.affiliation: Inserm, U1127, 75013 Paris, France.|CNRS, UMR 7225, 75013 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013 Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Bertolin
authors.affiliation: Inserm, U1127, 75013 Paris, France.|CNRS, UMR 7225, 75013 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013 Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Jacoupy
authors.affiliation: CHU Montpellier, Institute for Research in Biotherapy, Saint-Eloi Hospital, Montpellier, France.
authors.forename: S
authors.initials: S
authors.lastname: Traver
authors.affiliation: Inserm, U1127, 75013 Paris, France.|CNRS, UMR 7225, 75013 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013 Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Ferrando-Miguel
authors.affiliation: Inserm, U1127, 75013 Paris, France.|CNRS, UMR 7225, 75013 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013 Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Saint Georges
authors.affiliation: McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Grenier
authors.affiliation: Inserm, U1127, 75013 Paris, France.|CNRS, UMR 7225, 75013 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013 Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Ardila-Osorio
authors.affiliation: Inserm, U1127, 75013 Paris, France.|CNRS, UMR 7225, 75013 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013 Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: M-P
authors.initials: MP
authors.lastname: Muriel
authors.affiliation: Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Reta Lila Weston Institute for Neurological Studies, Institute of Neurology, University College London, London, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Lees
authors.affiliation: Laboratoire Chémogénétique Servier-Diverchim, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Gautier
authors.affiliation: Laboratoire Chémogénétique Servier-Diverchim, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Guedin
authors.affiliation: Laboratoire Chémogénétique Servier-Diverchim, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Coge
authors.affiliation: McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: E A
authors.initials: EA
authors.lastname: Fon
authors.affiliation: Inserm, U1127, 75013 Paris, France.|CNRS, UMR 7225, 75013 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013 Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Brice
authors.affiliation: Inserm, U1127, 75013 Paris, France.|CNRS, UMR 7225, 75013 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013 Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: O
authors.initials: O
authors.lastname: Corti
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D063269:Mitochondrial Turnover; D009154:Mutation; D010300:Parkinson Disease / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein