Chemical Biology Tools to Study Lipids and their Metabolism with Increased Spatial and Temporal Resolution.

Clémence Simon,Suihan Feng,Howard Riezman

doi:10.2533/chimia.2021.1012

Abstract

Lipids are important cellular components providing many essential functions. To fulfill these various functions evolution has selected for a diverse set of lipids and this diversity is seen at the organismal, cellular and subcellular level. Understanding how cells maintain this complex lipid organization is a very challenging problem, which for lipids, is not easily addressed using biochemical and genetic techniques. Therefore, chemical tools have an important role to play in our quest to understand the complexities of lipid metabolism. Here we discuss new chemical tools to study lipids, their distribution and metabolism with increased spatial and temporal resolution.

Highlights

Lipids are important cellular components providing many essential functions
The different fate of the same lipid precursor depending on its subcellular location is a demonstration that there is a metabolic bias for lipid metabolism based on subcellular location. This implies that lipids do not freely diffuse in cells, but follow precise pathways. These results demonstrated a new approach of tracking lipid metabolism with subcellular resolution and have the potential of being extending to other lipid molecules in the future
One major reason is due to the scarcity of techniques that are capable of modulating or tracking lipid activities with great precision

Summary

Metabolic reporter

Visualization/purification given time and in a non-invasive way.[33]. Caged analogues were developed for phosphoinositides,[34] lysophosphatidic acid,[35] glycerides,[36] ceramides,[37] or arachidonic acid,[38] and allowed their role in calcium signaling or translocation of proteins of specific lipid-binding domains to be studied. The current uncaging methods present a high temporal resolution due to the light control, the spatial resolution remains limited by the random distribution of molecules in cells. It is generally too difficult to focus light only in one subcellular compartment with current lasers and there is certainly insufficient resolution in the z-axis. Lipid metabolism, transport and function strongly depend on their subcellular location. Efforts were made in recent years to target the caged lipid to a specific organelle/subcellular place by adding a location tag on the protecting group.[33] Interestingly, Wagner et al designed a coumarinyl cage which could be decorated with different tags using a bioorthogonal click chemistry reaction, allowing to target either mitochondria, lysosomes, plasma membrane or the ER.[41]

Bifunctional lipid

Discussion and Concluding