1. The endoplasmic reticulum-mitochondria interface is perturbed in PARK2 knockout mice and patients with PARK2 mutations
- Author
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Stéphanie Bigou, Zoi Erpapazoglou, Clément A. Gautier, Vania Broccoli, Alexis Brice, Benjamin Foret, François Mouton-Liger, Carine Dalle, Delphine Bohl, Mathilde Girard, Sophie Duffaure, Florence Cormier, Jean-Christophe Corvol, Marie Paule Muriel, Olga Corti, Angelo Iannielli, Patrick P. Michel, 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), Institute of Stem Cell Therapy and Exploration of Monogenic Diseases, CNR Institute of Neuroscience, National Research Council [Italy] (CNR), San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), 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), 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)-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), and CHU Pitié-Salpêtrière [AP-HP]
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0301 basic medicine ,Ubiquitin-Protein Ligases ,Induced Pluripotent Stem Cells ,MFN2 ,Mitochondrion ,Biology ,Endoplasmic Reticulum ,medicine.disease_cause ,Parkin ,fibroblast ,mfn2 gene ,GTP Phosphohydrolases ,Mice ,03 medical and health sciences ,Cytosol ,Mitophagy ,Genetics ,medicine ,Animals ,Humans ,Calcium Signaling ,Molecular Biology ,Genetics (clinical) ,Mice, Knockout ,Mutation ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Endoplasmic reticulum ,park2 gene ,E3 Ubiquitin-Protein Ligase Parkin ,Parkinson Disease ,General Medicine ,Fibroblasts ,Molecular biology ,nervous system diseases ,mitochondria ,030104 developmental biology ,Gene Expression Regulation ,Mitochondrial biogenesis ,mutation - Abstract
International audience; Mutations in PARK2, encoding the E3 ubiquitin protein ligase Parkin, are a common cause of autosomal recessive Parkinson’s disease (PD). Loss of PARK2 function compromises mitochondrial quality by affecting mitochondrial biogenesis, bioenergetics, dynamics, transport and turnover. We investigated the impact of PARK2 dysfunction on the endoplasmic reticulum (ER)-mitochondria interface, which mediates calcium (Ca2+) exchange between the two compartments and is essential for Parkin-dependent mitophagy. Confocal and electron microscopy analyses showed the ER and mitochondria to be in closer proximity in primary fibroblasts from PARK2 knockout (KO) mice and PD patients with PARK2 mutations than in controls. Ca2+ flux to the cytosol was also modified, due to enhanced ER-to-mitochondria Ca2+ transfers, a change that was also observed in neurons derived from induced pluripotent stem cells of a patient with PARK2 mutations. Subcellular fractionation showed the abundance of the Parkin substrate mitofusin 2 (Mfn2), which is known to modulate the ER-mitochondria interface, to be specifically higher in the mitochondrion-associated ER membrane compartment in PARK2 KO tissue. Mfn2 downregulation or the exogenous expression of normal Parkin restored cytosolic Ca2+ transients in fibroblasts from patients with PARK2 mutations. In contrast, a catalytically inactive PD-related Parkin variant had no effect. Overall, our data suggest that Parkin is directly involved in regulating ER-mitochondria contacts and provide new insight into the role of the loss of Parkin function in PD development.
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