Very long-chain fatty acids drive 1-deoxySphingolipid toxicity
- Adam Majcher
- Gergely Karsai
- Elkhan Yusifov
- Martina Schaettin
- Ermanno Malagola
- Peter Horvath
- Jinmei Li
- Sofía Rodriguez-Gallardo
- Kuniyoshi Shimizu
- Gai Zhibo
- Raghvendra Dubey
- Tim Peterson
- Takeshi Harayama
- Thorsten Hornemann
2025-11-26
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.