Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging to Image Energy Metabolism

Researchers are working to overcome a challenge in the field of small molecule metabolite (SMM) detection, particularly those associated with energy metabolism. A new study, published in Analytical Chemistry uses matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and strategic solvent washes to image energy metabolism (1).

By removing interfering analytes causing ion suppression through solvent washes before matrix deposition, the scientists sought to improve SMM detection but also preserve the spatial localization of these crucial metabolites.

The findings highlight the key role of acidic methanol in significantly enhancing the detection of phosphate-containing metabolites directly linked to energy metabolism. This result stems from the elimination of lipids and highly polar metabolites responsible for ion suppression, as well as the denaturation of proteins, which releases bound phosphate-containing metabolites.

One of the notable applications of this methodology, referred to as iso-imaging, can be used for studying mouse kidney tissues. By using stable isotope infusions of [13C6]nicotinamide coupled with MALDI-MSI, researchers were able to identify distinct patterns within the kidney, including blood vessels, medulla, outer stripe, and cortex. Furthermore, they observed varying raw signals of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) across different regions of the kidney, offering insights into regional disparities in glucose metabolism. These disparities suggest that certain kidney regions favor either gluconeogenesis or glycolysis, two essential components of energy metabolism.

Gluconeogenesis is a metabolic process that synthesizes glucose from non-carbohydrate sources, primarily occurring in the liver and kidneys. Glycolysis is a cellular pathway that breaks down glucose into pyruvate, generating a small amount of ATP and NADH for energy production. Both gluconeogenesis and glycolysis are crucial in regulating blood sugar levels and ensuring the availability of glucose for living processes.

In addition to their work with the kidneys, the researchers extended their investigation to mouse muscle tissue. Using iso-imaging with [13C6]glucose, they discovered marked differences in glycolytic flux in different fiber types. The results revealed a high glycolytic flux from infused circulating glucose in type 1 and 2a fibers, such as the soleus, compared to relatively lower glycolytic flux in type 2b fibers, including the gastrocnemius.

By improving the detection of phosphate-containing metabolites using acidic methanol treatment and coupling it with isotope tracing, researchers have developed an enhanced method for probing energy metabolism. This could lead to potential advancements in the diagnosis and treatment of metabolic disorders.

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Reference

Lu, W.; Park, N. R.; TeSlaa, T.; Jankowski, C. S. R.; Samarah, L.; McReynolds, M.; Xing, X.; Schembri, J.; Woolf, M. T.; Rabinowitz, J. D.; Davidson, S. M. Acidic Methanol Treatment Facilitates Matrix-Assisted Laser Desorption Ionization-Mass Spectrometry Imaging of Energy Metabolism. Anal. Chem. 2023, 95 (40), 14879–14888. DOI:10.1021/acs.analchem.3c01875.