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| Home > Articles > Published articles > Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity |
(Institut d'Investigació Biomèdica de Bellvitge) (Institut d'Investigació Biomèdica de Bellvitge) (Institut d'Investigació Biomèdica de Bellvitge) (Institut d'Investigació Biomèdica de Bellvitge) (Institut de Ciències Fotòniques) (Centro de Investigaciones Biológicas "Margarita Salas") (Institut d'Investigació Biomèdica de Bellvitge)
| Date: | 2023 |
| 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. |
| Grants: | European Commission. Horizon 2020 871124 Instituto de Salud Carlos III PI20/00758 Ministerio de Economía y Competitividad CPII16/00016 Instituto de Salud Carlos III P118/00111 Instituto de Salud Carlos III FI18/00141 "la Caixa" Foundation 202006-30 |
| Note: | Altres ajuts: "Severo Ochoa" program for Centres of Excellence in R&D (CEX2019-000910-S [MCIN/AEI]) |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Published in: | The journal of clinical investigation, Vol. 133 Núm. 10 (may 2023) , ISSN 1558-8238 |
