Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity.

Carolina De La Torre, Aurora Pujol, Estela Area-Gómez, Manel Portero-Otin, Isidre Ferrer, Ali Fatemi, Àngels García-Cazorla, Pablo Loza-Alvarez, Maria Marsal, Antoinette Gelot, Laura Planas-Serra, Carlos Casasnovas, Stéphane Fourcade, Montserrat Ruiz, Natalia Juliá-Palacios, Cristina Jou, Bénédicte Heron, Leire Goicoechea, Nathalie Launay

Journal: The Journal of clinical investigation 2023;133(10):e162957

PMID: 36951944

Free Full Text on American Society for Clinical Investigation View on PubMed

Abstract

Sphingolipids function as membrane constituents and signaling molecules, with crucial roles in human diseases, from neurodevelopmental disorders to cancer, best exemplified in the inborn errors of sphingolipid metabolism in lysosomes. The dihydroceramide desaturase Δ4-dihydroceramide desaturase 1 (DEGS1) acts in the last step of a sector of the sphingolipid pathway, de novo ceramide biosynthesis. Defects in DEGS1 cause the recently described hypomyelinating leukodystrophy-18 (HLD18) (OMIM #618404). Here, we reveal that DEGS1 is a mitochondria-associated endoplasmic reticulum membrane-resident (MAM-resident) enzyme, refining previous reports locating DEGS1 at the endoplasmic reticulum only. Using patient fibroblasts, multiomics, and enzymatic assays, we show that DEGS1 deficiency disrupts the main core functions of the MAM: (a) mitochondrial dynamics, with a hyperfused mitochondrial network associated with decreased activation of dynamin-related protein 1; (b) cholesterol metabolism, with impaired sterol O-acyltransferase activity and decreased cholesteryl esters; (c) phospholipid metabolism, with increased phosphatidic acid and phosphatidylserine and decreased phosphatidylethanolamine; and (d) biogenesis of lipid droplets, with increased size and numbers. Moreover, we detected increased mitochondrial superoxide species production in fibroblasts and mitochondrial respiration impairment in patient muscle biopsy tissues. Our findings shed light on the pathophysiology of HLD18 and broaden our understanding of the role of sphingolipid metabolism in MAM function.

Address: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.; Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.; Department of Paediatric Neurology, Reference Centre for Neurogenetic Diseases, Armand Trousseau-La Roche Guyon University Hospital, and I2-D2 Federation, Sorbonne-Université, Paris, France.; Neurometabolic Unit and Synaptic Metabolism Lab, Neurology and Pathology Department, Institut Pediàtric de Recerca, Hospital Sant Joan de Déu, and MetabERN, Barcelona, Catalonia, Spain.; Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.; Josep Carreras Leukaemia Research Institute Barcelona, Catalonia, Spain.; Armand Trousseau-La Roche Guyon University Hospital, Sorbonne-Université, Paris, France.; ICFO-Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology, Castelldefels, Barcelona, Catalonia, Spain.; Departments of Neurology and Pediatrics, The Kennedy Krieger Institute, and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Pathology and Experimental Therapeutics, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.; Network Centre of Biomedical Research of Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.; Departament de Medicina Experimental, Universitat de Lleida-Institut de Recerca Biomedica de Lleida, Lleida, Catalonia, Spain.; Department of Neurology, Columbia University Medical Center, New York, New York, USA.; Centro de Investigaciones Biológicas "Margarita Salas," Madrid, Spain.; Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain.

DOI: 10.1172/JCI162957