Submitted by Penny Peck on Wed, 29/03/2023 - 14:44
The results of a collaborative research study recently published in Nature, with Dylan Ryan as co-corresponding author, identifies fumarate hydratase (FH) as a potential new therapeutic target for inflammatory diseases.
Macrophages are a frontline inflammatory cell type that are implicated in a range of diseases including Lupus, Arthritis, Sepsis and Covid-19. In the article, “Macrophage fumarate hydratase restrains mtRNA-mediated interferon production”, the authors explain how FH is repressed in macrophages. RNA is then released from mitochondria which can bind to key proteins ‘MDA5’ and ‘TLR7’ and trigger the release of cytokines, making the inflammation worse. In a model of sepsis, and in blood samples of patients suffering from Lupus, FH was shown to be repressed. Therefore, restoring FH or targeting MDA5 and TLR7 is an exciting prospect to be explored for the development of future anti-inflammatory therapies.
This study is a collaboration involving researchers of eight Universities, including the Murphy Group at the MRC MBU. The lead author, Professor Luke O’Neill, is Professor of Biochemistry at Trinity College, Dublin. Further details are available on the Trinity College Dublin website. In parallel the Frezza lab (Cologne) and Prudent Group (also at the MRC MBU) show in their article "Fumarate induces vesicular release of mtDNA to drive innate immunity” that FH loss triggers the release of mtDNA in a model of hereditary kidney cancer, a highly metastatic and aggressive tumour type, and may play a role cancer transformation and disease progression.
Figure: FH inhibition triggers IFN-β release via a mtRNA-driven retrograde response
Schematic depicting the mitochondrial retrograde signalling cascades occurring following FH inhibition during early-phase LPS signalling (left), and during late-phase LPS signalling in the absence of pharmacological or genetic targeting of FH (right). Created with BioRender.com.
Publication References:
Hooftman, A., Peace, C.G., Ryan, D.G. et al. Macrophage fumarate hydratase restrains mtRNA-mediated interferon production. Nature 615, 490–498 (2023). https://doi.org/10.1038/s41586-023-05720-6
Zecchini, V., Paupe, V, Herranz-Montoya, I. et al. Fumarate induces vesicular release of mtDNA to drive innate immunity. Nature 615, pages499–506 (2023). https://doi.org/10.1038/s41586-023-05770-w