A study led by Trinity College Dublin has uncovered potential new therapeutic targets for inflammatory or autoimmune diseases such as lupus, arthritis, sepsis and COVID-19.
The research, published in Nature, shows that an enzyme called fumarate hydratase is present at low levels in macrophages, a form of white blood cell, in the blood of people with systemic lupus erythematosus and also in a laboratory model of sepsis.
Fumarate, a chemical byproduct of mitochondrial metabolism, is known to trigger inflammation and has links to cancer. Fumarate hydratase acts to break down fumarate into malate. The researchers showed that when the enzyme is present at lower levels in cells, fumarate-triggered inflammation increases.
“No-one has made a link from fumarate hydratase to inflammatory macrophages before and we feel that this process might be targetable to treat debilitating diseases like lupus, which is a nasty autoimmune disease that damages several parts of the body including the skin, kidneys and joints,” said lead author Luke O’Neill, Professor of Biochemistry at Trinity College, in a press statement.
The team also found that when fumarate hydratase is repressed, either naturally or in the lab, mitochondria release RNA into the cell that can bind to two key immune proteins, MDA5 and TLR7, and trigger the release of cytokines, another type of inflammatory protein.
O’Neil and colleagues think fumarate could increase electrical potential across the mitochondrial membrane and therefore allow the release of its DNA or RNA, which they demonstrate as a possibility in their study.
“Restoring fumarate hydratase in these diseases or targeting MDA5 or TLR7… presents an exciting prospect for badly needed new anti-inflammatory therapies,” said O’Neill.
In another paper, also published in the same issue of Nature, Christian Frezza, a professor at the University of Cologne, and colleagues report that loss of fumarate hydratase activity in the kidney triggers oncogenic signaling. Frezza and team demonstrated that loss of fumarate hydratase changes mitochondrial morphology, releases mitochondrial DNA into the cell and triggers an inflammatory response.
“Because the system can go wrong in certain types of cancer, the scope of any potential therapeutic target could be widened beyond inflammation,” noted O’Neill.
Frezza and colleagues suggest a different mechanism for the escape of mitochondrial RNA or DNA into the cell to cause inflammation. Previous research shows that fumarate has the ability to change proteins by binding to cysteine residue, a process known as succination. They suggest that succination of mitochondrial proteins could lead to formation of small mitochondrial-derived vesicles allowing mitochondrial RNA to escape into the cell.
“These results reveal that increased levels of intracellular fumarate induce a remodelling of the mitochondrial network and the generation of mitochondrial-derived vesicles, which allows the release of mitochondrial DNA in the cytosol and subsequent activation of the innate immune response,” conclude Frezza and colleagues.
