Very long-chain fatty acids drive 1-deoxySphingolipid toxicity
1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids formed when serine palmitoyltransferase incorporates L-alanine instead of L-serine. Elevated 1-deoxySLs are associated with hereditary sensory neuropathy type 1 and diabetic neuropathy, but the molecular basis of their toxicity remains unclear. Here we show that toxicity is mediated by very long-chain (VLC) 1-deoxy-dihydroceramides (1-deoxyDHCer), particularly nervonyl-1-deoxyDHCer (m18:0/24:1) and lignoceryl-1-deoxyDHCer (m18:0/24:0). Using a CRISPR interference screen, we identify ELOVL1 and CERS2 as essential enzymes driving the formation of these toxic species. Genetic modulation or pharmacological inhibition of ELOVL1 prevents VLC 1-deoxyDHCer accumulation, rescuing the toxicity in cellular and neuronal models. Mechanistic studies reveal that m18:0/24:1 disrupts mitochondrial integrity and induces the mitochondrial permeability transition pore formation and BAX activation, leading to cell death. These findings establish a direct link between 1-deoxySL chemical structure and cytotoxicity and highlight ELOVL1 inhibition as a potential therapeutic strategy for 1-deoxySL-associated diseases.
Authors
- Raghvendra Dubey (ORCID: https://orcid.org/0000-0001-5749-0416)
- Sofía Rodriguez-Gallardo (ORCID: https://orcid.org/0000-0002-5189-5671)
- Timothy R. Peterson (ORCID: https://orcid.org/0000-0002-7749-7129)
- Peter J. Horvath (ORCID: https://orcid.org/0000-0002-7355-2936)
- T. HARAYAMA (ORCID: https://orcid.org/0000-0003-2255-4197)
- Martina Schaettin (ORCID: https://orcid.org/0000-0002-1487-6324)
- Gai Zhibo
- Thorsten Hornemann (ORCID: https://orcid.org/0000-0002-4218-1087)
- Gergely Karsai (ORCID: https://orcid.org/0000-0002-6840-682X)
- Adam Majcher
- Ermanno Malagola (ORCID: https://orcid.org/0000-0001-9294-3097)
- Elkhan Yusifov (ORCID: https://orcid.org/0000-0002-7227-839X)
- Jinmei Li
- Kuniyoshi Shimizu (ORCID: https://orcid.org/0009-0000-7215-7742)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Côte d'Azur (FR)
- University Hospital of Zurich (CH)
- Institut de Pharmacologie Moléculaire et Cellulaire (FR)
- Saint Louis University (US)
- Tokyo University of Agriculture and Technology (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-26
- DOI
- https://doi.org/10.1038/s41467-025-66687-8
- Primary Topic
- Sphingolipid Metabolism and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Centre National de la Recherche Scientifique
- National Center of Competence in Research Chemical Biology