Parkin maintains mitochondrial levels of the protective Parkinson’s disease-related enzyme 17-β hydroxysteroid dehydrogenase type 10

Autor: Andrew J. Lees, D. Guedin, Giulia Bertolin, H Ardila-Osorio, Alexis Brice, T Saint Georges, Sabine Traver, MP Muriel, F. Coge, Rosa Ferrando-Miguel, Clement A. Gautier, H Takahashi, Maxime Jacoupy, Olga Corti, Karl Grenier, Edward A. Fon
Přispěvatelé: Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Développement embryonnaire précoce humain et pluripotence EmbryoPluripotency (UMR 1203), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-CHU Montpellier, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Niigata University, Institute of Neurology [London], University College of London [London] (UCL), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Herrada, Anthony
Jazyk: angličtina
Rok vydání: 2015
Předmět:
MESH: Mutation
MESH: Rats
Mitochondrial Turnover
MESH: Mitochondria
Ubiquitin-Protein Ligases
Mitochondrial Degradation
PINK1
Biology
Mitochondrial Membrane Transport Proteins
Mitochondrial apoptosis-induced channel
Parkin
MESH: 3-Hydroxyacyl CoA Dehydrogenases
Mitochondrial Proteins
Mice
MESH: Brain
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
Animals
Humans
MESH: Animals
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
Molecular Biology
MESH: Mice
Original Paper
MESH: Humans
Ubiquitination
3-Hydroxyacyl CoA Dehydrogenases
Brain
MESH: Mitochondrial Proteins
Parkinson Disease
MESH: Mitochondrial Membrane Transport Proteins
Cell Biology
Molecular biology
MESH: Ubiquitin-Protein Ligases
MESH: Gene Expression Regulation
MESH: Mitochondrial Turnover
Mitochondria
Rats
nervous system diseases
Gene Expression Regulation
Mutation
DNAJA3
MESH: Ubiquitination
Mitochondrial fission
ATP–ADP translocase
MESH: Parkinson Disease
Zdroj: Cell Death and Differentiation
Cell Death and Differentiation, 2015, 22 (10), pp.1563-1576. ⟨10.1038/cdd.2014.224⟩
Cell Death and Differentiation, Nature Publishing Group, 2015, 22 (10), pp.1563-1576. ⟨10.1038/cdd.2014.224⟩
ISSN: 1350-9047
1476-5403
Popis: International audience; 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.
Databáze: OpenAIRE
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