Spastin regulates ER-mitochondrial contact sites and mitochondrial homeostasis
Amelie Raby,
Sonia Missiroli,
Peggy Sanatine,
Dominique Langui,
Julien Pansiot,
Nissai Beaude,
Lucie Vezzana,
Rachelle Saleh,
Martina Marinello,
Mireille Laforge,
Paolo Pinton,
Ana Buj-Bello,
Andrea Burgo
Affiliations
Amelie Raby
Genethon, 91000 Evry, France; Université Paris-Saclay, University Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, 91000 Evry, France
Sonia Missiroli
Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, and Technopole of Ferrara, Laboratory for Advanced Therapies (LTTA), 44121 Ferrara, Italy
Peggy Sanatine
Genethon, 91000 Evry, France
Dominique Langui
Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France
Julien Pansiot
Université Paris Cité, NeuroDiderot, Inserm, 75019 Paris, France
Nissai Beaude
Genethon, 91000 Evry, France; Université Paris-Saclay, University Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, 91000 Evry, France
Lucie Vezzana
Genethon, 91000 Evry, France; Université Paris-Saclay, University Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, 91000 Evry, France
Rachelle Saleh
Université Paris Cité, NeuroDiderot, Inserm, 75019 Paris, France
Martina Marinello
Genethon, 91000 Evry, France; Université Paris-Saclay, University Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, 91000 Evry, France
Mireille Laforge
Université Paris Cité, NeuroDiderot, Inserm, 75019 Paris, France
Paolo Pinton
Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, and Technopole of Ferrara, Laboratory for Advanced Therapies (LTTA), 44121 Ferrara, Italy
Ana Buj-Bello
Genethon, 91000 Evry, France; Université Paris-Saclay, University Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, 91000 Evry, France
Andrea Burgo
Genethon, 91000 Evry, France; Université Paris-Saclay, University Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, 91000 Evry, France; Corresponding author
Summary: Mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) emerged to play critical roles in numerous cellular processes, and their dysregulation has been associated to neurodegenerative disorders. Mutations in the SPG4 gene coding for spastin are among the main causes of hereditary spastic paraplegia (HSP). Spastin binds and severs microtubules, and the long isoform of this protein, namely M1, spans the outer leaflet of ER membrane where it interacts with other ER-HSP proteins. Here, we showed that overexpressed M1 spastin localizes in ER-mitochondria intersections and that endogenous spastin accumulates in MERCs. We demonstrated in different cellular models that downregulation of spastin enhances the number of MERCs, alters mitochondrial morphology, and impairs ER and mitochondrial calcium homeostasis. These effects are associated with reduced mitochondrial membrane potential, oxygen species levels, and oxidative metabolism. These findings extend our knowledge on the role of spastin in the ER and suggest MERCs deregulation as potential causes of SPG4-HSP disease.