Dimethyl Itaconate Is Not Metabolized into Itaconate Intracellularly
Mahmoud ElAzzouny1, Christopher T M B Tom2, Charles R Evans1
1From the Departments of Internal Medicine.
The Journal of Biological Chemistry
|February 12, 2017
Summary
Itaconic acid metabolism in macrophages remains unclear. This study found that while itaconic acid itself isn't taken up by cells, it can increase intracellular succinate, suggesting new avenues for research.
Area of Science:
- Immunology
- Metabolic Biochemistry
Background:
- Itaconic acid is a key metabolite produced by macrophages upon lipopolysaccharide (LPS) stimulation.
- The precise role of itaconic acid in the inflammatory cascade is not well understood.
Purpose of the Study:
- To investigate the metabolism of itaconic acid in cellular systems.
- To explore strategies for enhancing intracellular itaconic acid levels for further functional analysis.
Main Methods:
- Utilized stable isotope labeling with [13C]itaconate and dimethyl [13C]itaconate (DMI) to trace metabolic pathways.
- Monitored intracellular metabolite levels and assessed cellular uptake of labeled compounds.
Main Results:
- [13C]DMI was not metabolized into itaconic acid within the cells.
- [13C]Itaconic acid in the culture medium did not result in intracellular uptake but led to increased intracellular unlabeled succinate.
- No evidence of direct intracellular uptake of itaconic acid was observed.
Conclusions:
- Current methods using labeled itaconate or its dimethyl ester do not accurately reflect intracellular itaconic acid metabolism or uptake.
- Development of pro-drug strategies is crucial to increase intracellular itaconic acid concentrations for definitive studies on its biological functions in macrophages and other cell types.
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