Lennartz et al. evaluate lipid enrichment in clathrin-coated pits and observe that the differential lipid partitioning into clathrin-coated pits is largely driven by the lipid asymmetry of the plasma ...

Cell fate is shaped by external cues and intrinsic cellular states. While supracellular signals, such as growth factors, provide instructive guidance, emerging evidence highlights the role of cell-aut...

Ferroptosis is a form of cell death driven by iron-dependent lipid peroxidation, with specific lipid species playing key roles in modulating susceptibility. Among these, ether lipids have shown conflicting effects, being linked to both protection and sensitization. Here, we dissect the relationship between lipid structure and ferroptosis sensitivity and explain how ether lipids exert context-dependent effects. Ether lipids can promote ferroptosis through a metabolic bias towards the accumulation of polyunsaturated acyl chains and ethanolamine head groups, whereas this pro-ferroptotic tendency is counterbalanced by the anti-ferroptotic vinyl ether moiety introduced by plasmanylethanolamine desaturase 1. We show that this protective effect is critical for preventing ferroptosis in hiPSC-derived neurons, which accumulate otherwise pro-ferroptotic ether lipids during differentiation. This effect is not solely due to its antioxidant properties but also stems from the reprogramming of mitochondrial respiration. The lack of vinyl ether bonds leads to multiple mitochondrial defects, including increased mitochondrial reactive oxygen species (ROS), lower membrane potential, and abnormal cristae structures. These findings indicate that vinyl ether bonds in ether lipids offer dual ferroptosis resistance by scavenging ROS and minimizing its production at the mitochondrial level. The disruption of this system in Caenorhabditis elegans leads to iron-induced death and impaired motility. Thus, our study reveals ether lipid structural remodeling as a key regulator of ferroptosis sensitivity in neurons. ### Competing Interest Statement The authors have declared no competing interest. Deutsche Forschungsgemeinschaft, AS 647/1-1 Agencia Estatal de Investigación, PID2023-146930NB-I00 Japan Science and Technology Agency, JPMJER2101, JPMJFR230H, JPMJND2305, 25H01425, 25H01426, JPMJAP2505 National Research Agency French government, ANR-25-CE44-1525 Agencia Estatal de Investigación (AEI)-Spain, PID2021-123336NB-C21, PID2024-158644NB-C21 Swiss National Science Foundation, 185898, 184949 CNRS/Inserm ATIP-Avenir, ANR-15-IDEX-01

The Cell Dynamics and Fragmentation lab at We study how single cells move and fragment in complex environments using microfluidics. We bring tools and concep...

Eukaryotic cells synthesise thousands of lipid species, yet the principles that organise them across compartments remain unclear. Here we introduce PAP-SL, parallel (immuno)affinity purification coupl...

The lipid composition of cellular membranes is highly dynamic and undergoes continuous remodeling, affecting the biophysical properties critical to biological function. Here, we introduce an optical a...

GR-SCHUHMACHER

The Golgi complex serves as the central hub of the biosynthetic pathway, where anterograde and retrograde trafficking converge. How cargo and Golgi-resident proteins traverse this organelle has long b...