Mitochondrial morphology and cellular distribution are altered in SPG31 patients and are linked to DRP1 hyperphosphorylation
| Autor: | Christelle Tesson, Roman Serrat, Jean-William Dupuy, Nadège Bellance, Giovanni Stevanin, Julie Lavie, Rodrigue Rossignol, Cyril Goizet, Giovanni Benard, Alexandra Durr, Isabelle Coupry, Alexis Brice, Frédéric Darios, Didier Lacombe, Gilles Courtand |
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| Přispěvatelé: | Université de Bordeaux (UB), Centre Commun de Mesures Imagerie Cellulaire, Université de Lille, Sciences et Technologies, Centre Génomique Fonctionnelle Bordeaux [Bordeaux] (CGFB), Institut Polytechnique de Bordeaux-Université de Bordeaux Ségalen [Bordeaux 2], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-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), Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Physiopathologie mitochondriale, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), U1211 Laboratoire Maladies Rares: Génétique et Métabolisme, Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Laboratoire Maladies Rares : Génétique et Métabolisme [Bordeaux] (MRGM), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Dynamins Male [SDV]Life Sciences [q-bio] Phosphatase Hyperphosphorylation [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology Mitochondrion medicine.disease_cause GTP Phosphohydrolases Mitochondrial Proteins 03 medical and health sciences Mice 0302 clinical medicine Genetics medicine Phosphoprotein Phosphatases Animals Humans Phosphorylation Molecular Biology Genetics (clinical) Mitochondrial transport ComputingMilieux_MISCELLANEOUS Cells Cultured Cell Nucleus Neurons Mutation Spastic Paraplegia Hereditary Membrane Transport Proteins General Medicine Cell biology Mitochondria 030104 developmental biology Mitochondrial fission Ectopic expression Female Microtubule-Associated Proteins 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2017, pp.ddw425. ⟨10.1093/hmg/ddw425⟩ Human Molecular Genetics, 2017, pp.ddw425. ⟨10.1093/hmg/ddw425⟩ |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Hereditary spastic paraplegia, SPG31, is a rare neurological disorder caused by mutations in REEP1 gene encoding the microtubule-interacting protein, REEP1. The mechanism by which REEP1-dependent processes are linked with the disease is unclear. REEP1 regulates the morphology and trafficking of various organelles via interaction with the microtubules. In this study, we collected primary fibroblasts from SPG31 patients to investigate their mitochondrial morphology. We observed that the mitochondrial morphology in patient cells was highly tubular compared with control cells. We provide evidence that these morphological alterations are caused by the inhibition of mitochondrial fission protein, DRP1, due to the hyperphosphorylation of its serine 637 residue. This hyperphosphorylation is caused by impaired interactions between REEP1 and mitochondrial phosphatase PGAM5. Genetically or pharmacologically induced decrease of DRP1-S637 phosphorylation restores mitochondrial morphology in patient cells. Furthermore, ectopic expression of REEP1 carrying pathological mutations in primary neuronal culture targets REEP1 to the mitochondria. Mutated REEP1 proteins sequester mitochondria to the perinuclear region of the neurons and therefore, hamper mitochondrial transport along the axon. Considering the established role of mitochondrial distribution and morphology in neuronal health, our results support the involvement of a mitochondrial dysfunction in SPG31 pathology. |
| Databáze: | OpenAIRE |
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