PARIS, July 29 (Benin News) –
Mitochondria are known to be the powerhouses of cells, but growing evidence suggests they also play a role in inflammation. Scientists from the Salk Institute and the University of California in the United States have found a surprising link between mitochondrial DNA and an increased risk of atherosclerosis, which could pave the way for new therapies, according to the journal Immunity.
Researchers have examined human blood cells and found a surprising link between mitochondria, inflammation and the DNMT3A and TET2 genes, two genes that normally help regulate blood cell growth but are linked to an increased risk of atherosclerosis when mutated.
“We discovered that the DNMT3A and TET2 genes, in addition to their normal function of modifying chemical markers to regulate DNA, directly activate the expression of a gene involved in mitochondrial inflammatory pathways, suggesting a new molecular target for atherosclerosis- treatments,” says co-lead author Gerald Shadel, professor at Salk and director of the Nathan Shock Center of Excellence in the Basic Biology of Aging in San Diego.
The study began when researchers at UC San Diego observed a specific inflammatory response when examining the role of DNMT3A and TET2 mutations in clonal hematopoiesis — when mutated immature blood cells give rise to a population of mature blood cells with identical mutations.
They note that abnormal inflammatory signaling has also been linked to deficiencies of DNMT3A and TET2 in blood cells, which play important roles in the inflammatory response that promotes the progression of atherosclerosis. However, it has been unclear how the DNMT3A and TET2 genes are involved in inflammation and possibly atherosclerosis.
“The problem was that we couldn’t figure out how DNMT3A and TET2 were involved because the proteins they encode seem to do opposite things in terms of DNA regulation,” says co-author Christopher Glass, a professor at UC San Diego School of Medicine.
“Their antagonistic activity led us to believe that other mechanisms might be at play,” he adds. This prompted us to take a different approach and contact Shadel, who had discovered the same inflammatory pathway years earlier by studying mitochondrial DNA stress responses.
Within the mitochondria is a unique subset of the cell’s DNA that needs to be properly organized and condensed to maintain normal function. Shadel’s team previously studied the effects of mitochondrial DNA stress by turning off TFAM, a gene that helps mitochondrial DNA be packaged properly.
They found that when TFAM levels are reduced, mitochondrial DNA is squeezed out of the mitochondria in the cell. This sets off the same molecular alarm that signals the cell the presence of a bacterial or viral invader, triggering a defensive molecular pathway that promotes inflammation.
Scientists from Glass and Shadel’s labs worked together to better understand why mutations in DNMT3A and TET2 trigger inflammatory responses similar to those seen in mitochondrial DNA stress. They used genetic engineering and cell imaging tools to study cells from normal people with loss-of-function mutations in DNMT3A or TET2 expression and with atherosclerosis.
They found that experimentally reducing the expression of DNMT3A or TET2 in normal blood cells produced results similar to those seen in blood cells with loss-of-function mutations and in blood cells from patients with AD atherosclerosis: an increased inflammatory response.
Surprisingly, low expression levels of DNMT3A and TET2 in blood cells result in reduced expression of TFAM, which in turn leads to abnormal conditioning of mitochondrial DNA, causing inflammation due to the released mitochondrial DNA.
“We found that mutations in DNMT3A and TET2 impair their ability to bind and activate the TFAM gene,” recalls first author Isidoro Cobo, a postdoctoral fellow in Glass’s lab at UC San Diego. The absence or reduction of this binding activity results in the release of mitochondrial DNA and an overactive mitochondrial inflammatory response, and we believe this may exacerbate plaque formation in atherosclerosis.
“It’s very exciting to see that our discovery of TFAM deficiency, which causes stress and inflammation of mitochondrial DNA, is now directly linked to a disease like atherosclerosis,” said Shadel, holder of the Audrey Geisel Chair in Biomedical Sciences . Since we discovered this pathway, interest in mitochondrial involvement in inflammation has exploded, and many reports link mitochondrial DNA release to other clinical contexts.
Treatments that target inflammatory signaling pathways already exist for many other diseases. Glass and Shadel believe that blocking the pathways that worsen atherosclerosis in patients with mutations in TET2A and DNMT3A could lay the groundwork for new treatments. Scientists will now continue their research in this direction, examining the involvement of mitochondrial DNA in other human diseases and in aging.
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