Quantitative imaging of lipid transport in mammalian cells

• 成果类型: Article
• 署名作者: Iglesias-Artola, Juan M.; Boehlig, Kristin; Schuhmann, Kai; Cook, Katelyn C.; Lennartz, H. Mathilda; Schuhmacher, Milena; Barahtjan, Pavel; Lopez, Cristina Jimenez; Sachl, Radek; Garikapati, Vannuruswamy; Pombo-Garcia, Karina; Lohmann, Annett; Riegerova, Petra; Hof, Martin; Drobot, Bjorn; Shevchenko, Andrej; Honigmann, Alf; Nadler, Andre
• 署名单位: Max Planck Society; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Czech Academy of Sciences; J. Heyrovsky Institute of Physical Chemistry of the Czech Academy of Sciences; Helmholtz Association; Helmholtz-Zentrum Dresden-Rossendorf (HZDR); Technische Universitat Dresden; Technische Universitat Dresden
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09432-x
• 发表日期: 2025-10-09
• 关键词: cdc50 proteins; membrane; probes; MODEL

摘要

Eukaryotic cells produce over 1,000 different lipid species that tune organelle membrane properties, control signalling and store energy1,2. How lipid species are selectively sorted between organelles to maintain specific membrane identities is largely unclear, owing to the difficulty of imaging lipid transport in cells3. Here we measured the retrograde transport and metabolism of individual lipid species in mammalian cells using time-resolved fluorescence imaging of bifunctional lipid probes in combination with ultra-high-resolution mass spectrometry and mathematical modelling. Quantification of lipid flux between organelles revealed that directional, non-vesicular lipid transport is responsible for fast, species-selective lipid sorting, in contrast to the slow, unspecific vesicular membrane trafficking. Using genetic perturbations, we found that coupling between energy-dependent lipid flipping and non-vesicular transport is a mechanism for directional lipid transport. Comparison of metabolic conversion and transport rates showed that non-vesicular transport dominates the organelle distribution of lipids, while species-specific phospholipid metabolism controls neutral lipid accumulation. Our results provide the first quantitative map of retrograde lipid flux in cells4. We anticipate that our pipeline for mapping of lipid flux through physical and chemical space in cells will boost our understanding of lipids in cell biology and disease.