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 increased risk of atherosclerosis, which might 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 when mutated are associated at an increased risk of atherosclerosis.
“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, which suggests 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 UC San Diego researchers observed a specific inflammatory response as they investigated the roles 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 was also linked to deficiency of DNMT3A and TET2 in blood cells that play an important role in the inflammatory response that promotes the progression of atherosclerosis. But it was unclear how the DNMT3A and TET2 genes were involved in inflammation, and possibly in atherosclerosis.
“The problem was that we mightn’t figure out how DNMT3A and TET2 were involved because the proteins they encode do seemingly opposite things in terms of DNA regulation,” says co-author Christopher Glass, Professor at UC San Diego School of Medicine.
“Their antagonistic activity led us to think that other mechanisms might be at play,” he adds. This led us to take a different approach and contact Shadel, who had discovered the same inflammatory pathway years earlier by examining mitochondrial DNA stress responses.
Inside the mitochondria resides a unique subset of the cell’s DNA that must be properly organized and condensed to maintain normal function. Shadel’s team previously studied the effects of mitochondrial DNA stress by knocking out TFAM, a gene that helps ensure that mitochondrial DNA is properly packaged.
They found that when TFAM levels are reduced, mitochondrial DNA is pushed out of the mitochondria in the cell. This triggers the same molecular alarm that signals the cell to the presence of a bacterial or viral invader and triggers a defensive molecular pathway that promotes inflammation.
Scientists from the Glass and Shadel labs worked together to better understand why mutations in DNMT3A and TET2 trigger inflammatory responses similar to those seen during mitochondrial DNA stress. They applied genetic engineering and cell imaging tools to examine 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 had results similar to those obtained 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 lead to reduced expression of TFAM, which in turn leads to abnormal conditioning of mitochondrial DNA, causing inflammation due to 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’ 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 buildup in atherosclerosis.
“It is very exciting to see that our discovery of TFAM depletion, which causes mitochondrial DNA stress and inflammation, now has a direct relationship to a disease such as atherosclerosis,” says Shadel, holder of the the Audrey Geisel Chair in Biomedical Sciences. Since we revealed this pathway, interest in the involvement of mitochondria in inflammation has exploded, and many reports link mitochondrial DNA release to other clinical contexts.
Treatments targeting inflammation 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 might form the basis for new treatments. Scientists will now continue their research in this direction and study the involvement of mitochondrial DNA in other human diseases and in aging.
