Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity
Laura Planas-Serra, … , Estela Area-Gómez, Aurora Pujol
Laura Planas-Serra, … , Estela Area-Gómez, Aurora Pujol
Published March 23, 2023
Citation Information: J Clin Invest. 2023;133(10):e162957. https://doi.org/10.1172/JCI162957.
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Research Article Metabolism Neuroscience

Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity

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.

Authors

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

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Figure 8

Schematic representation of the pivotal role of DEGS1 in the regulation of MAM and mitochondria function.

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Schematic representation of the pivotal role of DEGS1 in the regulation ...
As a consequence of DEGS1 loss, an imbalance in SL metabolism (DhCer, Cer, DhSM, SM, DhHexCer, HexCer) occurs (Figure 6, D–G). Since SLs are essential components of membranes, mitochondrial and ER-MAM appear physically disrupted and thus functionally impaired. MAMs cannot be properly formed, since the distance between mitochondria and the ER is greater than in controls (Figure 6, H and I). Moreover, 2 hallmarks of MAM function, PL transport/synthesis and CE synthesis, are decreased (Figure 6, B and C). The MAM components DRP1 and DGAT2 (42, 59), have their function affected leading to (a) decreased mitochondrial fission (Figure 3, A–F) and (b) increased size and numbers of LDs (Figure 7, A–C) due to DGAT2’s main role in LD formation (68). Mitochondria appear larger in size and hyperfused (Figure 1D, Figure 2, and Figure 3, A–D), with OXPHOS impairment (Figure 1C, Table 1, and Supplemental Table 2), decreased membrane potential (Figure 3G), and augmented production of superoxide anion levels (Figure 3H).