ArticleThe Journal of clinical investigation2023
Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 35 citations in OpenAlex.
- Role of mitochondria-associated ER membranes in lipid metabolism: implications for renal lipotoxicity.Bioscience reports · 2026Review
- Congenital Disorders of Glycosphingolipid Biosynthesis: Ultrarare Severe Syndromes or Relatively Frequent Mild Neurocognitive Illnesses?Biomedicines · 2026Article
- Gypenoside XLIX and Mitochondria-Associated ER Membranes in Non-Alcoholic Fatty Liver Disease: Mechanistic Insights and Emerging Perspectives.Molecules (Basel, Switzerland) · 2026Review
- Single-cell and multi-omics analysis identifies mitophagy-related biomarkers and therapeutic targets in ischemic stroke.Scientific reports · 2026Article
- Developing a Metabolic-Associated Prognostic Index for Risk Stratification and Therapeutic Guidance in Stage I Lung Adenocarcinoma via Multiomics Analysis.JCO precision oncology · 2026Article
- An integrative approach to studying sphingolipid metabolism reveals p53 as a master regulator of the pathway.Journal of lipid research · 2026Article
- Mitochondria and Lipid Defects in Hereditary Progranulin-Related Frontotemporal Dementia.Cells · 2026Article
- SGCD: High-Resolution Spatial Domain Characterization via Data Interpolation and Cell-Type Deconvolution.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The complex web of membrane contact sites in brain aging and neurodegeneration.Cellular and molecular life sciences : CMLS · 2025Review
- Review
- Ceramide(d18:1/18:1)-NDUFA6 interaction inactivates respiratory complex I to attenuate oxidative-stress-driven pathogenesis in liver ischemia/reperfusion injury.JCI insight · 2025Article
- Effects of Th1/Th17 and Th2 cytokines on lipid metabolism in differentiated keratinocytes.Frontiers in physiology · 2025Article
- Role of lipids in interorganelle communication.Trends in cell biology · 2025Review
- Unravelling neuronal and glial differences in ceramide composition, synthesis, and sensitivity to toxicity.Communications biology · 2024Article
- Regulation of cellular and systemic sphingolipid homeostasis.Nature reviews. Molecular cell biology · 2024Review
- ER-mitochondria contact sites regulate hepatic lipogenesis via Ip3r-Grp75-Vdac complex recruiting Seipin.Cell communication and signaling : CCS · 2024Article
- ThemBio · 2024Article
- Mitochondria-Associated Membranes in Aging and Senescence.Aging and disease · 2024Review
- A-Syn(ful) MAM: A Fresh Perspective on a Converging Domain in Parkinson's Disease.International journal of molecular sciences · 2024Review
- Sphingolipids: Less Enigmatic but Still Many Questions about the Role(s) of Ceramide in the Synthesis/Function of the Ganglioside Class of Glycosphingolipids.International journal of molecular sciences · 2024Review
Corrections and comments
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Authors and funding
19 authors at 10 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.