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162957.3-20230524143950-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf (8.54 MB)

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2023-05-23

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cc by (c) Planas Serra, Laura et al, 2022
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/199881

Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity

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https://doi.org/10.1172/JCI162957

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 Delta 4-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.

Subject

Mitocondris, Bioenergètica

Subject (English)

Mitochondria, Bioenergetics

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Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Patologia i Terapèutica Experimental)

Citation

PLANAS SERRA, Laura, et al. Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity. Journal of Clinical Investigation. 2023. Vol. 133, num. 10. ISSN 1558-8238. [consulted: 16 of August of 2026]. Available at: https://hdl.handle.net/2445/199881

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