Lipids are troublesome to detect with gentle microscopy. Utilizing a brand new chemical labeling technique, a Dresden-based workforce 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 approach will assist perceive the function of lipid transport in well being and illness. The findings have been printed 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 info.
Each cell can create 1000’s of various lipids, and when they’re out of stability, metabolic and neurodegenerative ailments can come up. It’s nonetheless not nicely understood how cells kind various kinds of lipids between cell organelles to keep up the composition of every membrane.
A serious cause is that lipids are troublesome to check, since microscopy methods to exactly hint their location inside cells have thus far 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 technique that permits visualizing lipids in cells utilizing normal fluorescence microscopy.
After the primary profitable proof of idea, the duo introduced mass-spectrometry knowledgeable 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 check how lipids are transported between mobile organelles.
Synthetic lipids beneath the sunbed
“We began our venture with synthesizing a set of minimally modified lipids that signify the primary lipids current in organelle membranes. These modified lipids are primarily the identical as their native counterparts, with only a few completely different atoms that allowed us to trace them beneath the microscope,” explains Kristin Böhlig, a Ph.D. pupil 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 implies 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 residing 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 therapy 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 alternate between cell membrane and organelle membranes,” concludes Kristin.
With a purpose to perceive the microscopy knowledge, the workforce 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 circulation via 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 finished by Drobot on the HZDR, the analysis workforce 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, moderately than by vesicles.
This non-vesicular transport is way 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 instances quicker than by vesicles. These outcomes indicate that the lipid compositions of organelle membranes are primarily maintained via 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 through the transport from the cell membrane to the organelle membrane.
A lift for lipids in cell biology and illness
This new method gives the first-ever quantitative map of how lipids transfer via the cell to completely different organelles. The outcomes recommend that non-vesicular lipid transport has a key function within the upkeep of every organelle membrane composition.
Honigmann, analysis group chief on the BIOTEC, says, “Our lipid-imaging approach permits the mechanistic evaluation of lipid transport and performance straight in cells, which has been inconceivable earlier than. We predict that our work opens the door to a brand new period of learning the function of lipids throughout the cell.”
Imaging of lipids will permit additional discoveries and assist to disclose the underlying mechanisms in ailments attributable to lipid imbalances. The brand new approach might doubtlessly 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, seems again in the beginning of the research: “Imaging lipids in cells has at all times been one of the crucial difficult elements of microscopy. Our venture 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 shortly determined to go for it.
“It nonetheless took us nearly 5 years from the beginning of the venture to the purpose in autumn 2019 when the 2 of us lastly produced a pattern with a lovely plasma membrane stain. That’s after we knew that we have been onto one thing large. As a reward, sure well-known international occasions meant we have been required to close down our laboratories a number of months later.
“In the long run, the delay was for the most effective. Earlier than the revolution in the usage of synthetic intelligence in picture segmentation, we’d not have been capable of correctly quantify the imaging knowledge, so our conclusions would have been way more restricted.”
Researchers nonetheless want to find out which lipid-transfer proteins drive the selective transport of various lipid species. In addition they must establish the power sources that energy lipid transport and make sure that every organelle retains its personal distinctive membrane composition.
Extra info: Juan M. Iglesias-Artola et al, Quantitative imaging of lipid transport in mammalian cells, Nature (2025). DOI: 10.1038/s41586-025-09432-x
