Koomen David C, May Jody C, Mansueto Alexander J, Graham Todd R, McLean John A
Center for Innovative Technology, Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.
Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235, United States.
J Am Soc Mass Spectrom. 2024 Oct 2;35(10):2448-2457. doi: 10.1021/jasms.4c00251. Epub 2024 Sep 14.
Global discovery lipidomics can provide comprehensive chemical information toward understanding the intricacies of metabolic lipid disorders such as dyslipidemia; however, the isomeric complexity of lipid species remains an analytical challenge. Orthogonal separation strategies, such as ion mobility (IM), can be inserted into liquid chromatography-mass spectrometry (LC-MS) untargeted lipidomic workflows for additional isomer separation and high-confidence annotation, and the emergence of high-resolution ion mobility (HRIM) strategies provides marked improvements to the resolving power ( > 200) that can differentiate small structural differences characteristic of isomers. One such HRIM strategy, high-resolution demultiplexing (HRdm), utilizes multiplexed drift tube ion mobility spectrometry (DTIMS) with post-acquisition algorithmic deconvolution to access high IM resolutions while retaining the measurement precision inherent to the drift tube technique; however, HRdm has yet to be utilized in untargeted studies. In this manuscript, a proof-of-concept study using ATP10D dysfunctional murine models was investigated to demonstrate the utility of HRdm-incorporated untargeted lipidomic analysis pipelines. Total lipid features were found to increase by 2.5-fold with HRdm compared to demultiplexed DTIMS as a consequence of more isomeric lipids being resolved. An example lipid, PC 36:5, was found to be significantly higher in dysfunctional ATP10D mice with two resolved peaks observed by HRdm that were absent in both the functional ATP10D mice and the standard demultiplexed DTIMS acquisition mode. The benefits of utilizing HRdm for discerning isomeric lipids in untargeted workflows have the potential to enhance our analytical understanding of lipids related to disease complexity and biologically relevant studies.
全球发现脂质组学能够提供全面的化学信息，有助于理解诸如血脂异常等代谢性脂质紊乱的复杂性；然而，脂质种类的异构体复杂性仍然是一个分析挑战。正交分离策略，如离子淌度（IM），可插入液相色谱-质谱联用（LC-MS）非靶向脂质组学工作流程中，以实现额外的异构体分离和高可信度注释，而高分辨率离子淌度（HRIM）策略的出现显著提高了分辨能力（>200），能够区分异构体特有的微小结构差异。其中一种HRIM策略，即高分辨率解复用（HRdm），利用多路复用漂移管离子淌度光谱法（DTIMS）和采集后算法去卷积来获得高IM分辨率，同时保留漂移管技术固有的测量精度；然而，HRdm尚未应用于非靶向研究。在本论文中，我们进行了一项概念验证研究，使用ATP10D功能失调的小鼠模型来证明结合HRdm的非靶向脂质组学分析流程的实用性。与解复用的DTIMS相比，由于更多的异构体脂质被解析，发现使用HRdm时总脂质特征增加了2.5倍。发现一种示例脂质PC 36:5在功能失调的ATP10D小鼠中显著更高，通过HRdm观察到两个解析峰，而在功能正常的ATP10D小鼠和标准解复用DTIMS采集模式中均未出现。在非靶向工作流程中利用HRdm识别异构体脂质的好处有可能增强我们对与疾病复杂性相关脂质的分析理解以及生物学相关研究。
