By During this new study, researchers have discovered how the function of mitochondria, and dysfunction, played an important role in many diseases, and even aging.
In a new study published in the immune edition, scientists at the Faculty of Medicine, California University, San Diego and Salk Institute for Biological Studies, reported a surprising relationship between mitochondria, inflammation and DNMT3A and Tet2, a pair of genes that usually help regulate blood cell growth, but When mutating, it is associated with an increased risk of atherosclerosis.
“We found that the DNMT3A and Tet2 genes, in addition to their normal work in changing chemical tags to regulate DNA, directly activated the expression of the genes involved in the mitochondrial inflammatory pathway, which hinted as a new molecular target for atherosclerosis therapy,” Geralduler said as a new molecular for Therapeutic arapeutic atherosclerosis, “said the new Geralduler for atherosclerosis,” for atherosculosis. Co-Senior and Director of San Diego Nathan Shock Center of Excellence in the basic biology of aging at the Salk Institute. “They also interact with the mitochondrial inflammatory pathway, which signaled a new molecular target for atherosclerosis therapy.”
When studying the role of DNMT3A and TET2 mutations in clonal hematopoiesis, which occurs when stem cells begin to make new blood cells with the same genetic mutations, the author of the Christopher Glass Co-Siniors, MD, PhD, Professor in the Department of Medicine and molecular drugs in UC San Diego Medical School, and his colleagues note that abnormal inflammatory reign atherosclerosis development.
But the question remains how the DNMT3A and TET2 genes are involved in inflammation and atherosclerosis – a buildup of fat plaque in the arteries and the main causes of cardiovascular disease. It is estimated that about half of Americans are between 45 and 84 have atherosclerosis, which is the only main cause of death in the United States and westernized countries.
“The problem is that we cannot find out how DNMT3A and Tet2 are involved because the protein they code seems to do the opposite things about DNA regulations,” Glass said. “Their antagonist activity makes us believe that there may be other mechanisms that play a role, which encourages us to take a different approach and contact Shadel, which has revealed the same inflammatory path for many years before checking the response to mitochondrial DNA stress.”
What they found
Inside the mitochondria are in the unique subset of cell DNA that must be arranged and condensed correctly to maintain normal functions. The shadel team had previously investigated the stress effect of mitochondrial DNA by removing tfam, a gene that helped ensure mitochondrial DNA was packaged properly.
Shadel and his colleagues determine that when tfam levels are reduced, mitochondrial DNA is removed from the mitochondria to the interior of the cell, triggers the same molecular alarm that reminds cells to bacterial or viral invaders and triggers defensive molecular pathways that trigger inflammatory responses.
Glass’ laboratories and shadel work together to better understand why DNMT3A and TET2 mutations cause inflammatory responses that are similar to those observed during mitochondrial DNA stress. The team applies genetic engineering and cell imaging devices to examine cells from people with normal cells, those who lose function mutations in the expression of DNMT3A or Tet2 and those who have atherosclerosis.
They found that experimentally reduced the expression of DNMT3A or Tet2 in normal blood cells produced results similar to blood cells that lost the mutation of function and blood cells of atherosclerosis patients. In all three cases, there is an increase in inflammatory response.
They also observed that the low level of expression of DNMT3A and TET2 in blood cells caused a decrease in TFAM expression, which in turn caused abnormal mitochondrial DNA packaging, triggers inflammation due to the mitochondrial DNA released.
“We found that the DNMT3A and TET2 mutations prevent their ability to bind and activate the TFAM gene,” said the first writer Isidoro Cobo, PhD, a postdoctoral scholar in the glass laboratory. “Missing or reducing this binding activity causes the release of mitochondrial DNA and the response of mitochondrial inflammation that is too active. We believe this can worsen the accumulation of plaque in atherosclerosis.”
Shadel said this finding expanded and deepened understanding of the function of mitochondria and its role in disease.
“It is very pleasant to see our discovery of TFAM thinning which causes stress for mitochondrial DNA and inflammation now has direct relevance for diseases such as atherosclerosis,” Shadel said. “Since we revealed this pathway, there has been an explosion of interest in the mitochondria involved in inflammation and many reports connect the release of mitochondrial DNA with other clinical contexts.