Scientists Finally Capture Elusive Lipids in Action Inside Cells

A new imaging method is helping scientists understand how lipids, or fats, are organized inside cell membranes. These membranes are not just simple barriers. They are complex landscapes with tiny patches called nanodomains. Here, lipids and proteins work together for vital cell tasks like communication and transport.

Scientists have mapped protein behavior in these areas. However, lipids have been much harder to track. Lipids move very quickly within membranes. This makes them difficult to see with traditional imaging tools. This new method helps fill in the gaps in understanding how these molecules are arranged and how they help cells function.

Tracking Lipids in 3D

To solve this problem, scientists created "bifunctional lipid probes." These special molecules look like natural lipids. But they have chemical features that allow them to be tracked.

Inside living cells, light can "lock" these probes in place. This stops lipid movement at a specific moment. Researchers then add fluorescent tags. This makes it possible to see where different lipid types were located without disturbing the cell.

Even with these probes, standard light microscopy cannot show the fine details of cell membranes. Electron microscopy offers much higher resolution. But it cannot track specific molecules.

Correlative light and electron microscopy (CLEM) combines both methods. It links molecular labeling with detailed structural images. When used with lipid probes, this method is called Lipid-CLEM. It shows both where lipids are and how membranes are organized at a microscopic level.

Earlier versions of CLEM had problems. Some damaged delicate membrane structures. Others only worked on the cell surface. Many could not tell different lipid types apart.

Mathilda Lennartz and her team improved the technique. They are from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Germany and the Weizmann Institute of Science in Israel. Their new method is called Lipid-CLEM.

Lennartz, a lead author of the study, explained their process. To study lipid sorting in early endosomes, cells must be frozen quickly. This stops lipids and preserves the cell membrane. Then, lipids can be labeled on very thin slices of the sample using click chemistry. These slices are then imaged with Lipid-CLEM.

"With Lipid-CLEM, we saw that a specific lipid called sphingomyelin is more common in small vesicles inside the endosome," Mathilda said. "It is less common in tubular membrane domains. This separation has also been seen for some proteins."

She added that this means some lipids, like proteins, must also be sorted in the endosome. Sphingomyelin and a protein cargo arrive at the early endosome at the same time. But they separate into different domains. This shows that lipid and protein paths can differ during sorting.

The Power of Teamwork

Ori Avinoam's team at the Weizmann Institute helped with correlative light and electron microscopy. Ori noted that this study shows how important collaborations are for research. Combining different expertises helped them create a method to uncover basic principles of lipid sorting that were previously unknown.

André Nadler, a corresponding author, summarized the findings. He said their Lipid-CLEM workflow allows 3D viewing of lipid densities in membrane nanodomains. This offers a new way to study lipid organization in complex cell structures. They can finally look at lipid sorting in membranes with the needed resolution.

Nadler believes their new method will help them better understand how lipids work in cells. It allows them to study both lipids and proteins together during membrane organization and function. This may also help understand diseases related to membrane problems.

Deep Dive & References

Visualizing suborganellar lipid distribution using correlative light and electron microscopy - Nature Cell Biology, 2026