Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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 Article has an altmetric score of 7

Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity

  • Text
  • PDF
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 7

Neutral lipids and PA accumulation and their regulation.

Options: View larger image (or click on image) Download as PowerPoint
Neutral lipids and PA accumulation and their regulation.
(A) Representat...
(A) Representative microscopy images of Oil Red O, an esterified cholesterol and LD marker, counterstained with hematoxylin as a nuclear marker, and its (B) Feret’s diameter and (C) number/cell quantification. DEGS1 patient (n = 5) and control (n = 5) fibroblasts. (D) PA and glyceride levels. DEGS1 patient (n = 4) and control (n = 4) fibroblasts. mRNA levels of (E) genes encoding key enzymes involved in the LD synthesis pathway DGKA, DGAT1, and DGAT2, and (F) the lipogenic gene master regulators SREBF1a, SREBF1c, and SREBF2. DEGS1 patient (n = 4–5) and control (n = 5) fibroblasts. (G) mRNA levels of SREBF target genes involved in cholesterol synthesis: HMGCS1, HMGCR, MVD, and SQLE. DEGS1 patient (n = 4) and control (n = 4) fibroblasts. (H) CE/FC lipid ratio and (I) PS, PE, and PC lipid levels in human fibroblasts from patients with DEGS1 mutations (n = 4–5) and control individuals (n = 4–5). All experiments were done in triplicate. Data are presented as box-and-whisker plots (median, interquartile interval, minimum, maximum). *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed Student’s t test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 12 X users
23 readers on Mendeley
See more details