Illustration of red blood cells moving through clogged artery to indicate cholesterol build up as a result of homozygous familial hypercholesterolemia and atherosclerosis
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Researchers at the Salk Institute and UC San Diego (UCSD) report in new finding published today in the journal Immunity, that they have uncovered a link between mitochondria, inflammation, and two genes that normally help regulate blood cell growth—DNMT3A and TET2— that, when mutated, are associated with an increased risk of atherosclerosis.

“We found that the genes DNMT3A and TET2, in addition to their normal job of altering chemical tags to regulate DNA, directly activate expression of a gene involved in mitochondrial inflammatory pathways, which hints at a new molecular target for atherosclerosis therapeutics,” said Gerald Shadel, a Salk professor and co-senior author.

The findings came about when UCSD researchers noted a specific inflammatory response while investigating 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 reported that abnormal inflammatory signaling was also related to DNMT3A and TET2 deficiency in blood cells that play a major role in inflammation response that promotes the progression of atherosclerosis, though exactly how the two genes were involved in inflammation and potentially atherosclerosis is unknown.

“The problem was we couldn’t work out how DNMT3A and TET2 were involved because the proteins they code do seemingly opposite things regarding DNA regulation,” noted Christopher Glass, co-senior author and professor at the UC San Diego School of Medicine. “Their antagonistic activity led us to believe there may be other mechanisms at play. This prompted us to take a different approach and contact Shadel, who had uncovered the same inflammatory pathway years earlier while examining responses to mitochondrial DNA stress.”

In the earlier research into mitochondrial DNA stress, Shadel’s team removed a gene, TFAM, which helps to ensure that mitochondrial DNA is packaged correctly in order to maintain normal functioning. When levels of TFAM were reduced, the investigators found that mitochondrial DNA is expelled from the mitochondria into the interior of the cell, and activity that signals the cell there is a presence of bacteria or a virus and triggers an immune response that promotes inflammation.

In the current research, the UCSD and Salk teams joined forces to try to understand why mutations in the DNMT3A or TET2 genes led to a similar inflammatory response as seen in the research into mitochondrial stress.

The team discovered that reducing the expression of DNMT3A or TET2 in the normal blood cells produced a similar response of blood cells that had loss of function mutations and blood cells from atherosclerosis patients—an increased inflammatory response.

“We discovered that DNMT3A and TET2 mutations prevent their ability to bind and activate the TFAM gene,” said first author Isidoro Cobo, a postdoctoral researcher in the Glass lab at UCSD. “Missing or reducing this binding activity leads to mitochondrial DNA release and an overactive mitochondrial inflammation response, and we believe this may exacerbate plaque buildup in atherosclerosis.”

Therapeutics that target inflammation signaling pathways already exist for other diseases. Glass and Shadel believe that blocking pathways that exacerbate atherosclerosis in patients with TET2A and DNMT3A mutations could form the basis for new treatments.

“It’s very exciting to see our discovery on TFAM depletion causing mitochondrial DNA stress and inflammation now has direct relevance for a disease like atherosclerosis,” noted Shadel. “Ever since we revealed this pathway, there has been an explosion of interest in mitochondria being involved in inflammation and many reports linking mitochondrial DNA release to other clinical contexts.”

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