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Dresden research team develops novel imaging approach to visualize individual lipids in cells and uncovers the main transport mechanism for lipids within the cell.
To the point:
New technique to image single lipids: Lipids are notoriously difficult to detect with light microscopy. Using a new chemical labeling strategy, the Dresden team has overcome this limitation, enabling novel insights into where specific lipids are located and how they are transported in cells.
Map of lipid flow: The researchers used the new lipid imaging method to answer the long-standing question how cells transport specific lipids to their target organelle membranes. The study revealed that non-vesicular lipid transport by proteins is the primary mechanism that maintains the membrane composition of specific organelles.
Understanding the role of lipids in diseases: Lipid imbalances play a role in several metabolic or neurodegenerative diseases. The new lipid-imaging technique will help understand the role of lipid transport in health and disease. The identification of the proteins involved in selective lipid transport can accelerate further discoveries of new drug targets for lipid-associated diseases.
Lipid molecules, or fats, are crucial to all forms of life. Cells need lipids to build membranes, separate and organize biochemical reactions, store energy, and transmit information. Every cell can create thousands of different lipids, and when they are out of balance, metabolic and neurodegenerative diseases can arise. It is still not well understood how cells sort different types of lipids between cell organelles to maintain the composition of each membrane. A major reason is that lipids are difficult to study, since microscopy techniques to precisely trace their location inside cells have so far been missing.
In a long-standing collaboration André Nadler, a chemical biologist at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany teamed up with Alf Honigmann, a bioimaging specialist at Biotechnology Center (BIOTEC) at the TUD Dresden University of Technology, to develop a method that enables visualizing lipids in cells using standard fluorescence microscopy. After the first successful proof of concept, the duo brought mass-spectrometry expert Andrej Shevchenko (MPI-CBG), Björn Drobot at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR), and the group of Martin Hof from the J. Heyrovsky Institute of Physical Chemistry in Prague on board to study how lipids are transported between cellular organelles.
Artificial lipids under the sunbed
“We started our project with synthesizing a set of minimally modified lipids that represent the main lipids present in organelle membranes. These modified lipids are essentially the same as their native counterparts, with just a few different atoms that allowed us to track them under the microscope,” explains Kristin Böhlig, a PhD student in the Nadler group and chemist who was in charge of creating the modified lipids.
The modified lipids mimic natural lipids and are “bifunctional,” which means they can be activated by UV light, causing the lipid to bind or crosslink with nearby proteins. The modified lipids were loaded in the membrane of living cells and, over time, transported into the membranes of organelles. The researchers worked with human cells in cell culture, such as bone or intestinal cells, as they are ideal for imaging.
“After the treatment with UV light, we were able to monitor the lipids with fluorescence microscopy and capture their location over time. This gave us a comprehensive picture of lipid exchange between cell membrane and organelle membranes,” concludes Kristin.
In order to understand the microscopy data, the team needed a custom image analysis pipeline. “To address our specific needs, I developed an image analysis pipeline with automated image segmentation assisted by artificial intelligence to quantify the lipid flow through the cellular organelle system,” says Juan Iglesias-Artola, who did the image analysis.
Speedy lipid transport by proteins
By combining the image analysis with mathematical modeling, done by Björn Drobot at the HZDR, the research team discovered that between 85% and 95% of the lipid transport between the membranes of cell organelles is organized by carrier proteins that move the lipids, rather than by vesicles. This non-vesicular transport is much more specific with regard to individual lipid species and their sorting to the different organelles in the cell. The researchers also found that the lipid transport by proteins is ten times faster than by vesicles. These results imply that the lipid compositions of organelle membranes are primarily maintained through fast, species-specific, non-vesicular lipid transport.
In a parallel set of experiments, the group of Andrej Shevchenko at the MPI-CBG used ultra-high-resolution mass spectrometry to see how the different lipids change their structure during the transport from the cell membrane to the organelle membrane.
A boost for lipids in cell biology and disease
This new approach provides the first-ever quantitative map of how lipids move through the cell to different organelles. The results suggest that non-vesicular lipid transport has a key role in the maintenance of each organelle membrane composition.
Alf Honigmann, research group leader at the BIOTEC says, “Our lipid-imaging technique enables the mechanistic analysis of lipid transport and function directly in cells, which has been impossible before. We think that our work opens the door to a new era of studying the role of lipids within the cell.”
Imaging of lipids will allow further discoveries and help to reveal the underlying mechanisms in diseases caused by lipid imbalances. The new technique could potentially help to develop new druggable targets and therapeutic approaches for lipid-associated diseases, such as nonalcoholic fatty liver disease.
“We knew that we were onto something big”
André Nadler, research group leader at MPI-CBG, looks back at the start of the study, “Imaging lipids in cells has always been one of the most challenging aspects of microscopy. Our project was no different. Alf Honigmann and I started discussing about solving the lipid imaging problem as soon as we got hired in close succession at MPI-CBG in 2014/15 and we quickly decided to go for it. It still took us almost five years from the start of the project to the point in autumn 2019 when the two of us finally produced a sample with a beautiful plasma membrane stain. That’s when we knew that we were onto something big. As a reward, certain well known global events meant we were required to shut down our laboratories a few months later. In the end, the delay was for the best. Before the revolution in the use of artificial intelligence in image segmentation, we would not have been able to properly quantify the imaging data, so our conclusions would have been much more limited.”
Researchers still need to determine which lipid-transfer proteins drive the selective transport of different lipid species. They also need to identify the energy sources that power lipid transport and ensure that each organelle keeps its own unique membrane composition.
Dr. André Nadler
Email: nadler@mpi-cbg.de
Prof. Alf Honigmann
Email: alf.honigmann@tu-dresden.de
Juan M. Iglesias-Artola, Kristin Böhlig, Kai Schuhmann, Katelyn C. Cook, H. Mathilda Lennartz, Milena Schuhmacher, Pavel Barahtjan, Cristina Jiménez López, Radek Šachl, Vannuruswamy Garikapati, Karina Pombo-Garcia, Annett Lohmann, Petra Riegerová, Martin Hof, Björn Drobot, Andrej Shevchenko, Alf Honigmann, and André Nadler: Quantitative imaging of lipid transport in mammalian cells. Nature (August 2025). https://doi.org/10.1038/s41586-025-09432-x
https://www.mpi-cbg.de/news-outreach/news-media/article/fat-microscopy-imaging-l... - Press release
A microscope picture of human bone cells (U2OS) showing the localization of a lipid (phosphatidyleth ...
Copyright: Kristin Böhlig and Juan Iglesias-Artola / Nature (2025) / MPI-CBG
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