In a recent study, researchers discovered how the function and dysfunction of mitochondria plays a critical role in many diseases, and even in aging. In a new study published in the online issue of Immunity, scientists from the University of California San Diego School of Medicine and the Salk Institute for Biological Studies report a surprising link between mitochondria, inflammation and DNMT3A and TET2, a pair of genes that normally help regulate blood cell growth, but when mutated they are associated with an increased risk of atherosclerosis.
“We found that the DNMT3A and TET2 genes, in addition to their normal job of modifying chemical tags to regulate DNA, directly activate the expression of a gene involved in mitochondrial inflammatory pathways, which seems to be a new molecular target for atherosclerosis therapeutics,” said Gerald Shadel, PhD, study co-lead author and director of the San Diego Nathan Shock Center of Excellence in the Basic Biology of Aging at the Salk Institute. “They also interact with mitochondrial inflammatory pathways, suggesting a novel molecular target for atherosclerosis therapeutics.” While studying the roles of DNMT3A and TET2 mutations in clonal hematopoiesis, which occurs when stem cells begin making new blood cells with the same genetic mutation, study co-lead author Christopher Glass, MD, PhD, Professor in the Departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine and colleagues noted that abnormal inflammatory signaling related to DNMT3A and TET2 deficiency in blood cells played a major role in the inflammatory response that promotes the development of atherosclerosis.
But the question remained as to how the DNMT3A and TET2 genes were involved in inflammation and atherosclerosis – the buildup of fatty plaques in the arteries and the main underlying cause of cardiovascular disease. It is estimated that about half of Americans between the ages of 45 and 84 suffer from atherosclerosis, which is the leading cause of death in the United States and Westernized countries. “The problem was that we couldn’t figure out how DNMT3A and TET2 were involved because the proteins they encode apparently do opposite things when it comes to DNA regulation,” Glass said. “Their antagonistic activity led us to believe that there might be other mechanisms at play, which prompted us to take a different approach and contact Shadel, who had discovered the same inflammatory pathway years earlier during examining mitochondrial DNA stress responses.”
What they discovered Inside the mitochondria resides a unique subset of the cell’s DNA that must be organized and condensed correctly to maintain normal function. Shadel’s team had previously studied the effects of mitochondrial DNA stress by deleting TFAM, a gene that helps ensure that mitochondrial DNA is properly conditioned.
Shadel and his colleagues determined that when TFAM levels are reduced, mitochondrial DNA is expelled from the mitochondria into the cell interior, triggering the same molecular alarms that alert cells to a bacterial or viral invader and trigger a defensive molecular pathway that triggers an inflammatory response. The Glass and Shadel labs worked together to better understand why DNMT3A and TET2 mutations led to inflammatory responses similar to those seen during mitochondrial DNA stress. The teams applied genetic engineering and cell imaging tools to examine cells from people with normal cells, those with loss-of-function mutations in DNMT3A or TET2 expression, and those with atherosclerosis.
They found that experimentally reducing the expression of DNMT3A or TET2 in normal blood cells produced similar results to blood cells with loss-of-function mutations and blood cells from patients with atherosclerosis. In all three cases, there was an increased inflammatory response. They also observed that low levels of DNMT3A and TET2 expression in blood cells led to reduced expression of TFAM, which in turn led to abnormal mitochondrial DNA conditioning, causing inflammation due to to released mitochondrial DNA.
“We found that the DNMT3A and TET2 mutations impede their ability to bind and activate the TFAM gene,” said first author Isidoro Cobo, PhD, a postdoctoral researcher in Glass’ lab. “The absence or reduction of this binding activity results in the release of mitochondrial DNA and an overactive mitochondrial inflammatory response. We believe this may exacerbate plaque buildup in atherosclerosis.” Shadel said the findings broaden and deepen the understanding of mitochondrial function and their role in disease.
“It’s very exciting to see our discovery of TFAM depletion causing mitochondrial DNA stress and inflammation now have direct relevance to a disease like atherosclerosis,” Shadel said. “Since we revealed this pathway, there has been an explosion of interest in the mitochondria involved in inflammation and many reports linking mitochondrial DNA release to other clinical contexts.” (ANI)
(This story has not been edited by the Devdiscourse team and is auto-generated from a syndicated feed.)