Itaconate is a naturally occurring organic acid and a metabolic byproduct found in various biological systems. It is classified as a dicarboxylic acid, meaning it contains two carboxyl groups. While it has been known since 1836, its roles in mammalian biology have only recently been uncovered, revealing its presence and activity within cells.
How Cells Make Itaconate
Cells primarily produce itaconate within immune cells, particularly macrophages, when they are activated by inflammatory stimuli. Itaconate synthesis begins with cis-aconitate, an intermediate molecule in the tricarboxylic acid (TCA) cycle, which is a central pathway for energy production in cells. The enzyme responsible for this conversion is Aconitate Decarboxylase 1 (ACOD1), also known as Immune-Responsive Gene 1 (IRG1). ACOD1/IRG1 diverts a portion of the TCA cycle’s intermediates to produce itaconate, essentially acting as a “break” in the cycle. This diversion leads to the accumulation of itaconate within the mitochondria, where it is produced, and then transported into the cell’s cytosol.
Itaconate’s Role in Inflammation
Itaconate demonstrates potent anti-inflammatory properties, serving as a significant regulator of the immune response. It inhibits key inflammatory pathways within cells. For instance, itaconate can reduce the activity of the NF-κB pathway, a central regulator of inflammatory gene expression. It also suppresses the activation of inflammasomes, protein complexes that trigger the release of pro-inflammatory signaling molecules.
Itaconate plays a role in “reprogramming” macrophage metabolism and function. It can shift macrophages from a pro-inflammatory state (M1) towards a more regulatory or anti-inflammatory state (M2). This metabolic shift involves inhibiting succinate dehydrogenase (SDH), an enzyme in the TCA cycle, leading to succinate buildup, a metabolite that influences inflammation. Itaconate’s actions also activate transcription factors like Nrf2 and ATF3, promoting genes involved in antioxidant and anti-inflammatory responses.
Beyond Inflammation: Itaconate’s Other Functions
Beyond modulating inflammation, itaconate exhibits other biological activities. It possesses antimicrobial properties, inhibiting the growth of certain bacteria and viruses. Itaconate achieves this by interfering with bacterial enzymes, such as isocitrate lyase, which is essential for the metabolism of some pathogens. This inhibition can disrupt bacterial growth, particularly when bacteria rely on specific carbon sources.
Itaconate also influences cellular metabolism, impacting processes like glycolysis, oxidative phosphorylation, and fatty acid oxidation. It can inhibit glycolysis, a pathway for glucose breakdown, and affect the energy metabolism of cells. Itaconate possesses antioxidant properties, helping to reduce cellular oxidative stress.
Itaconate’s Potential in Health and Medicine
Understanding the diverse roles of itaconate holds promise for developing new strategies in human health and medicine. Its anti-inflammatory effects suggest potential for new treatments for various inflammatory diseases, including autoimmune conditions like rheumatoid arthritis and systemic lupus erythematosus, as well as conditions such as sepsis and psoriasis. Research is exploring itaconate or its derivatives as therapeutic agents to mitigate excessive inflammation and tissue damage.
The antimicrobial capabilities of itaconate also open avenues for addressing infectious diseases. By inhibiting metabolic enzymes in pathogens, itaconate could offer a novel approach to combat bacterial and viral infections. Its influence on cellular metabolism and antioxidant properties indicate potential relevance in metabolic disorders and cancer research, where immunomodulatory effects could be beneficial. Ongoing studies are investigating how manipulating itaconate levels or its pathways could lead to improved therapeutic outcomes in a range of challenging conditions.