Mij
Senior Member (Voting Rights)
Abstract
The discovery of itaconate as an immunoregulatory metabolite has transformed the field of immunometabolism and opened multiple therapeutic avenues over the past decade. While the immunological functions of itaconic acid have been extensively studied, several aspects of its biochemistry—particularly in vivo utilization pathways—have remained unclear. In a recent study published in Nature Metabolism, Willenbockel et al apply carbon tracing to uncover the metabolic fate of itaconate within the organism. Insights from this work have important implications for understanding the physiological roles of itaconate and for advancing itaconate-based therapeutic strategies.
In response to itaconate injection, the authors reported rapid and dynamic changes in the plasma metabolome, with the levels of itaconate, mesaconate, citramalate, and succinate displaying matching dynamic profiles. They also noted a progressive increase in plasma levels of methylmalonate and BCAA. Taken together, these findings support previous observations on itaconate’s impact on SDH and MUT activity. ¹³C tracing enabled authors to further follow the metabolic fate of itaconate in vivo.
Strikingly, in contrast to what was observed in hepatocarcinoma cell lines, the authors revealed a swift and substantial conversion of itaconate into acetyl-CoA in mouse liver, followed by engagement in the carnitine shuttle and subsequent incorporation into the TCA cycle and amino acids. Organ-level metabolic profiling provided key insights (Figure 1): while itaconate accumulated prominently in the heart, lungs, kidneys, and liver, its metabolic impact varied across tissues. Based on SDH activity (succinate/fumarate ratio), the proportion of itaconate-derived citrate, and the levels of its derivatives, mesaconate and citramalate, the authors showed that itaconate is actively metabolized in the liver and kidneys, while simultaneously suppressing SDH in those tissues.
Willenbockel et al Paper here
The discovery of itaconate as an immunoregulatory metabolite has transformed the field of immunometabolism and opened multiple therapeutic avenues over the past decade. While the immunological functions of itaconic acid have been extensively studied, several aspects of its biochemistry—particularly in vivo utilization pathways—have remained unclear. In a recent study published in Nature Metabolism, Willenbockel et al apply carbon tracing to uncover the metabolic fate of itaconate within the organism. Insights from this work have important implications for understanding the physiological roles of itaconate and for advancing itaconate-based therapeutic strategies.
In response to itaconate injection, the authors reported rapid and dynamic changes in the plasma metabolome, with the levels of itaconate, mesaconate, citramalate, and succinate displaying matching dynamic profiles. They also noted a progressive increase in plasma levels of methylmalonate and BCAA. Taken together, these findings support previous observations on itaconate’s impact on SDH and MUT activity. ¹³C tracing enabled authors to further follow the metabolic fate of itaconate in vivo.
Strikingly, in contrast to what was observed in hepatocarcinoma cell lines, the authors revealed a swift and substantial conversion of itaconate into acetyl-CoA in mouse liver, followed by engagement in the carnitine shuttle and subsequent incorporation into the TCA cycle and amino acids. Organ-level metabolic profiling provided key insights (Figure 1): while itaconate accumulated prominently in the heart, lungs, kidneys, and liver, its metabolic impact varied across tissues. Based on SDH activity (succinate/fumarate ratio), the proportion of itaconate-derived citrate, and the levels of its derivatives, mesaconate and citramalate, the authors showed that itaconate is actively metabolized in the liver and kidneys, while simultaneously suppressing SDH in those tissues.
Willenbockel et al Paper here