Lipids are tough to detect with gentle microscopy. Utilizing a brand new chemical labeling technique, a Dresden-based staff led by André Nadler on the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) and Alf Honigmann on the Biotechnology Heart (BIOTEC) of TU Dresden has overcome this limitation, enabling new insights into lipids.
The researchers have been capable of reply a long-standing query: how do cells transport particular lipids to the membranes of their goal organelles? The brand new lipid-imaging method will assist perceive the position of lipid transport in well being and illness. The findings have been revealed within the journal Nature.
Lipid molecules, or fat, are essential to all types of life. Cells want lipids to construct membranes, separate and set up biochemical reactions, retailer power, and transmit data.
Each cell can create hundreds of various lipids, and when they’re out of steadiness, metabolic and neurodegenerative ailments can come up. It’s nonetheless not properly understood how cells kind several types of lipids between cell organelles to take care of the composition of every membrane.
A serious cause is that lipids are tough to review, since microscopy methods to exactly hint their location inside cells have to this point been lacking.
In a long-standing collaboration, Nadler, a chemical biologist on the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany, teamed up with Honigmann, a bioimaging specialist at Biotechnology Heart (BIOTEC) on the TU-Dresden College of Know-how, to develop a way that permits visualizing lipids in cells utilizing commonplace fluorescence microscopy.
After the primary profitable proof of idea, the duo introduced mass-spectrometry skilled Andrej Shevchenko (MPI-CBG), Björn Drobot on the Helmholtz-Zentrum Dresden-Rossendorf (HZDR), and the group of Martin Hof from the J. Heyrovsky Institute of Bodily Chemistry in Prague on board to review how lipids are transported between mobile organelles.
Synthetic lipids beneath the sunbed
“We began our mission with synthesizing a set of minimally modified lipids that signify the principle lipids current in organelle membranes. These modified lipids are primarily the identical as their native counterparts, with just some completely different atoms that allowed us to trace them beneath the microscope,” explains Kristin Böhlig, a Ph.D. scholar within the Nadler group and chemist who was in command of creating the modified lipids.
The modified lipids mimic pure lipids and are “bifunctional,” which suggests they are often activated by UV gentle, inflicting the lipid to bind or crosslink with close by proteins. The modified lipids have been loaded within the membrane of dwelling cells and, over time, transported into the membranes of organelles. The researchers labored with human cells in cell tradition, corresponding to bone or intestinal cells, as they are perfect for imaging.
“After the remedy with UV gentle, we have been capable of monitor the lipids with fluorescence microscopy and seize their location over time. This gave us a complete image of lipid trade between cell membrane and organelle membranes,” concludes Kristin.
With a view to perceive the microscopy information, the staff wanted a customized picture evaluation pipeline. “To handle our particular wants, I developed a picture evaluation pipeline with automated picture segmentation assisted by synthetic intelligence to quantify the lipid stream by the mobile organelle system,” says Juan Iglesias-Artola, who did the picture evaluation.
Speedy lipid transport by proteins
By combining the picture evaluation with mathematical modeling accomplished by Drobot on the HZDR, the analysis staff found that between 85% and 95% of the lipid transport between the membranes of cell organelles is organized by service proteins that transfer the lipids, quite than by vesicles.
This non-vesicular transport is rather more particular with regard to particular person lipid species and their sorting to the completely different organelles within the cell. The researchers additionally discovered that the lipid transport by proteins is ten occasions sooner than by vesicles. These outcomes suggest that the lipid compositions of organelle membranes are primarily maintained by quick, species-specific, non-vesicular lipid transport.
In a parallel set of experiments, the group of Shevchenko on the MPI-CBG used ultra-high-resolution mass spectrometry to see how the completely different lipids change their construction in the course of the transport from the cell membrane to the organelle membrane.
A lift for lipids in cell biology and illness
This new method offers the first-ever quantitative map of how lipids transfer by the cell to completely different organelles. The outcomes recommend that non-vesicular lipid transport has a key position within the upkeep of every organelle membrane composition.
Honigmann, analysis group chief on the BIOTEC, says, “Our lipid-imaging method permits the mechanistic evaluation of lipid transport and performance immediately in cells, which has been unattainable earlier than. We expect that our work opens the door to a brand new period of finding out the position of lipids throughout the cell.”
Imaging of lipids will permit additional discoveries and assist to disclose the underlying mechanisms in ailments brought on by lipid imbalances. The brand new method might probably assist to develop new druggable targets and therapeutic approaches for lipid-associated ailments, corresponding to nonalcoholic fatty liver illness.
‘We knew that we have been onto one thing large’
Nadler, analysis group chief at MPI-CBG, appears again initially of the research: “Imaging lipids in cells has all the time been one of the crucial difficult features of microscopy. Our mission was no completely different. Alf Honigmann and I began discussing about fixing the lipid imaging drawback as quickly as we obtained employed in shut succession at MPI-CBG in 2014/15 and we rapidly determined to go for it.
“It nonetheless took us virtually 5 years from the beginning of the mission to the purpose in autumn 2019 when the 2 of us lastly produced a pattern with a stupendous plasma membrane stain. That’s once we knew that we have been onto one thing large. As a reward, sure well-known world occasions meant we have been required to close down our laboratories a couple of months later.
“Ultimately, the delay was for the very best. Earlier than the revolution in the usage of synthetic intelligence in picture segmentation, we’d not have been capable of correctly quantify the imaging information, so our conclusions would have been rather more restricted.”
Researchers nonetheless want to find out which lipid-transfer proteins drive the selective transport of various lipid species. In addition they must determine the power sources that energy lipid transport and be sure that every organelle retains its personal distinctive membrane composition.
Extra data: Juan M. Iglesias-Artola et al, Quantitative imaging of lipid transport in mammalian cells, Nature (2025). DOI: 10.1038/s41586-025-09432-x