Lipidomics Research: High-Resolution Ion-Mobility Mass Spectrometry Unravels Lipid Isomers

A group of scientists are using high-resolution ion mobility–mass spectrometry (HRIM–MS) to analyze lipid isomers. The research, published in the Journal of the American Society for Mass Spectrometry, could help further our understanding of the roles of specific lipids in various biological processes (1).

Lipids are crucial molecules in biology, with diverse functions ranging from energy storage to cell signaling. However, their structural diversity poses a formidable challenge for scientists trying to decipher their specific biological roles, primarily due to the presence of numerous isomers, or molecules with the same molecular formula but distinct structural arrangements. This complexity has been a longstanding challenge in lipidomics research.

The traditional approach to analyzing lipids, liquid chromatography-mass spectrometry (LC–MS), often falls short in differentiating between isomeric and isobaric lipid species in complex biological samples. This limitation has hindered the comprehensive understanding of lipid function in various biological contexts.

To overcome this challenge, researchers have turned to multidimensional liquid chromatography–ion mobility–mass spectrometry (LC–IM–MS) analysis. This approach offers improved separation capabilities and is particularly well-suited for studying lipids with intricate structures. However, certain forms of lipid isomerism, such as double-bond positional isomers and regioisomers, present structural similarities that cannot be resolved by conventional ion mobility techniques.

In the study, the researchers evaluated the performance of a high-resolution ion mobility (HRIM) system based on structures for lossless ion manipulation (SLIM) technology. This system was coupled with a high-resolution quadrupole time-of-flight (QTOF) analyzer to tackle the complex issue of lipidomic isomerism. The SLIM technology extends the ion path to approximately 13 meters, allowing for improved separation of isomeric features.

The researchers demonstrated the power of HRIM–MS by successfully dissecting isomeric phosphatidylcholine (PC) standards that differed only in double-bond (DB) and stereospecific number (SN) positions. Notably, the separation of protonated DB isomers was significantly enhanced when they were analyzed as metal adducts. For sodium adducts, the system achieved close to baseline separation of three different PC 18:1/18:1 isomers with distinct cis-double bond locations. Similarly, it effectively resolved PC 18:1/18:1 (cis-9) from the corresponding PC 18:1/18:1 (trans-9) form. The system's separation capacity was further enhanced when using silver ion doping, enabling the baseline separation of regioisomers that could not be resolved when measured as sodium adducts.

The researchers assessed the sensitivity and reproducibility of their approach and benchmarked its performance on more complex mixtures by identifying PC isomers in total brain and liver lipid extracts.

HRIM–MS opens new avenues for understanding the functions of specific lipids in health and disease. This technology could have far-reaching implications for fields ranging from medicine to biochemistry, with potential applications in drug development, biomarker discovery, and personalized medicine.

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References

Kedia, K.; Harris, R.; Ekroos, K.; Moser, K. W.; DeBord, D.; Tiberi, P.; Goracci, L.; Zhang, N. R.; Wang, W.; Spellman, D. S.; Bateman, K. Investigating Performance of the Slim-Based High Resolution Ion Mobility Platform for Separation of Isomeric Phosphatidylcholine Species. Journal of the American Society for Mass Spectrometry 2023, 34 (10), 2176–2186. DOI:10.1021/jasms.3c00157.