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.
View: Text | PDF
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

×

Figure 6

DEGS1 impairment leads to MAM disruption.

Options: View larger image (or click on image) Download as PowerPoint
DEGS1 impairment leads to MAM disruption. (A) Schematic representation o...
(A) Schematic representation of PL synthesis and trafficking and cholesterol esterification at the MAM. (B) PL synthesis and trafficking assay. 3H-PS/3H-PE lipid ratio reflecting incorporation after 12 hours of 3H-serine into 3H-PS and 3H-PE in human fibroblasts from patients with DEGS1 mutations (n = 3) and control individuals (n = 3). (C) SOAT1 activity assay. 3H-CE lipid levels reflecting the incorporation of 3H-cholesterol into 3H-CE after 6 hours in human fibroblasts from patients with DEGS1 mutations (n = 4) and control individuals (n = 5). (D and E) DhCer/cer, DhSM/SM, and (F and G) DhHexCer/HexCer lipid levels in the total and MAM fractions from fibroblasts of patients with DEGS1 mutations (n = 3–5) and control individuals (n = 4–5). (H) Distance between the ER and the mitochondria (M) in fibroblasts using TEM and its (I) quantification. DEGS1 patient (n = 3) and control (n = 3) fibroblasts. Data are represented as box-and-whisker plots (median, interquartile interval, minimum, maximum). *P < 0.05; **P < 0.01, 2-tailed Student’s t test.