Mitochondrial Metabolite and Inflammatory Reactions Linked

Category Health

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A new study has revealed a link between a mitochondrial metabolite and an inflammatory response, which could be the trigger for cancer and autoimmune diseases. It was found that fumarate, an oncogenic metabolite, causes mitochondrial damage and the release of mitochondrial DNA and RNA, leading to an immune response that causes inflammation.

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A groundbreaking study has uncovered a link between a mitochondrial metabolite and the triggering of an inflammatory response. As essential components of our cells, mitochondria play a crucial role in performing various tasks such as chemical reactions that are necessary for cell functioning. One of these functions is the production of energy, which is vital for cell growth and replication. However, any alterations in the chemical reactions within the mitochondria can result in the development of diseases.

FH (Fumarate Hydratase) is naturally produced by the mitochondria

For example, a shortage of fumarate hydratase (FH) in the Krebs cycle, a key metabolic pathway in the mitochondria, leads to a severe form of kidney cancer in humans. The absence of FH results in a buildup of the molecule fumarate, which is a contributing factor to cancer development. Hence, fumarate is referred to as an oncogenic metabolite or simply an "oncometabolite." .

The research team led by Alexander von Humboldt Professor Dr. Christian Frezza, formerly at the University of Cambridge (United Kingdom) and now at the CECAD Cluster of Excellence for Aging Research at the University of Cologne, has now developed a new mouse and cell model together with the research group led by Professor Prudent of the University of Cambridge to deepen the understanding of aggressive kidney cancer.

Aggressive forms of kidney cancer in humans are caused by the lack of FH

In the models, the silencing of the fumarate hydratase gene can be temporally controlled by the scientists. Using a combination of high-resolution imaging techniques and precise biochemical experiments, the scientists have shown that fumarate causes mitochondrial damage. This in turn releases the genetic material of the mitochondria in small vesicles called mitochondrial-derived vesicles.

These vesicles filled with mitochondrial DNA (mtDNA) and RNA (mtRNA) trigger an immune reaction that eventually leads to inflammation. The study was recently published in the journal Nature.

Fumarate is the oncogenic metabolite generated when FH is lacking

"Our study shows for the first time a correlation between a mitochondrial metabolite and the onset of inflammation, which could be the trigger for cancer and autoimmune diseases," said Professor Frezza. "Based on these findings, we can now work on new approaches to treat patients, which will hopefully lead to the development of new therapeutic strategies to treat cancer patients in the future." .

In addition, a group at Trinity Biomedical Sciences Institute in Dublin led by Professor Luke O’Neill in collaboration with Christian Frezza’s research group has described a similar mechanism in macrophages. Macrophages are cells of the body that are responsible for eliminating harmful microbes. Here, the researchers found that mitochondrial RNA released by the macrophages’ mitochondria, rather than DNA, is the main trigger of in-vivo inflammation.

Mitochondrial vesicles released from damaged cells can cause an immune response

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