What is Fumarate?
If you’re a fan of immunology, chances are you’ve been seeing a lot of recent buzz about fumarate’s role in inflammation. So what is fumarate, exactly? This molecule is produced during one of the intermediate steps of the TCA Cycle (aka the Krebs Cycle) in the mitochondria during cellular respiration.
However, it is well-established that the intermediate molecules produced in the TCA Cycle often play multiple roles other than cellular energy production. Some intermediates can be “siphoned off” to replenish the building blocks of certain amino acids, and recent evidence now suggests a role for fumarate as an immune signaling molecule.
Fumarate, Mitochondria, and Inflammation
In back-to-back papers published in Nature, two research groups uncovered novel roles for fumarate in mitochondria-driven inflammation activation. Using a combination of cutting-edge research techniques including RNA-seq, both groups found that fumarate accumulation in the mitochondria (caused by blocking the enzyme that converts fumarate to malate) leads to the release of mitochondrial DNA and RNA into the cell.
If you didn’t know already, mitochondria have their own genome (mtDNA) separate from the cell’s normal genome. Although the two groups propose alternate hypotheses for the exact mechanism of how fumarate accumulation stimulates mtDNA and mtRNA release, the findings were overwhelmingly clear that the ultimate downstream effect was the activation of interferon I (IFN-I), a major activator of the immune system.
The discovery of this novel role for fumarate in regulating mitochondria/immune signaling has a number of interesting therapeutic research implications. A major biomarker of a tumor’s likelihood of a positive response to immunotherapy is the level of immune infiltration of the tumor, and IFN-I signaling is a major marker for immune-infiltrated tumors. Certain kinds of cancer, hereditary leiomyomatosis, and renal cell cancer (HLRCC) often have mutations in fumarate hydratase, leading to fumarate accumulation and high IFN-I signaling. Stimulation of mtDNA release by targeting fumarate hydratase could be a promising target to improve immunotherapy responses.
Possibilities extend to inflammatory diseases as well. Although a study to confirm the link needs to be carried out, Hooftman et. al. found that people with the autoimmune disease systemic lupus erythematosus (SLE) have suppressed fumarate hydratase activity. SLE is already characterized by high levels of IFN-I inflammation and increased circulating mtDNA, so a link to fumarate seems plausible as an explanation.
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Jane Cook, Biochemist & Content Writer, Bridge Informatics
Jane Cook, the leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email [email protected] or [email protected].