Mitochondria are organelles found inside most cells, best known for generating the chemical energy required to power cellular functions. Increasingly, nonetheless, researchers are discovering how mitochondrial function -; and dysfunction -; play critical roles in quite a few diseases, and even aging.

In a recent study published within the August 4, 2022 online issue of Immunity, scientists at University of California San Diego School of Medicine and 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, are related to an increased risk of atherosclerosis.

We found that the genes DNMT3A and TET2, along with their normal job of altering chemical tags to manage DNA, directly activate expression of a gene involved in mitochondrial inflammatory pathways, which hints as a recent molecular goal for atherosclerosis therapeutics. Additionally they interact with mitochondrial inflammatory pathways, which hints at a recent molecular goal for atherosclerosis therapeutics.”

Gerald Shadel, PhD, co-senior study writer and director of the San Diego Nathan Shock Center of Excellence within the Basic Biology of Aging at Salk Institute

While studying the roles of DNMT3A and TET2 mutations in clonal hematopoiesis, which happens when stem cells begin making recent blood cells with the identical genetic mutation, co-senior study writer Christopher Glass, MD, PhD, professor within 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 significant role within the inflammation response that promotes development of atherosclerosis.

However the query remained how DNMT3A and TET2 genes were involved in inflammation and atherosclerosis -; the buildup of fatty plaques in arteries and the first underlying reason for heart problems. It’s estimated roughly half of Americans between the ages of 45 and 84 have atherosclerosis, which is the one leading reason for death in america and westernized nations.

“The issue was we couldn’t work out how DNMT3A and TET2 were involved since the proteins they code seemingly do opposite things regarding DNA regulation,” said Glass. “Their antagonistic activity led us to imagine there could also be other mechanisms at play, which prompted us to take a special approach and make contact with Shadel, who had uncovered the identical inflammatory pathway years earlier while examining responses to mitochondrial DNA stress.”

What they found

Inside mitochondria resides a novel subset of the cell’s DNA that should be organized and condensed appropriately to sustain normal function. Shadel’s team had previously investigated the consequences of mitochondrial DNA stress by removing TFAM, a gene that helps ensure mitochondrial DNA is packaged appropriately.

Shadel and colleagues determined that when TFAM levels are reduced, mitochondrial DNA is expelled from mitochondria into the cell’s interior, setting off the identical molecular alarms that alert cells to a bacterial or viral invader and trigger a defensive molecular pathway that prompts an inflammatory response.

Glass’ and Shadel’s labs worked together to raised understand why DNMT3A and TET2 mutations led to inflammatory responses just like those observed during mitochondrial DNA stress. The teams applied genetic engineering tools and cell imaging to look at cells from individuals with normal cells, those with lack of function mutations in DNMT3A or TET2 expression and people with atherosclerosis.

They found that experimentally reducing the expression of DNMT3A or TET2 in normal blood cells produced similar results to blood cells that had lack of function mutations and to blood cells from atherosclerosis patients. In all three cases, there was an increased inflammatory response.

Additionally they observed that low levels of DNMT3A and TET2 expression in blood cells led to reduced TFAM expression, which in turn led to abnormal mitochondria DNA packaging, instigating inflammation as a result of released mitochondrial DNA.

“We discovered that DNMT3A and TET2 mutations prevent their ability to bind and activate the TFAM gene,” said first writer Isidoro Cobo, PhD, a postdoctoral scholar in Glass’ lab. “Missing or reducing this binding activity results in mitochondrial DNA release and an overactive mitochondrial inflammation response. We imagine this will likely exacerbate plaque buildup in atherosclerosis.”

Shadel said the findings broaden and deepen understanding of mitochondrial function and their role in disease.

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

Therapeutics that focus on inflammation signaling pathways exist already for a lot of other diseases. Glass and Shadel imagine that blocking pathways that exacerbate atherosclerosis in patients with TET2A and DNMT3A mutations could form the premise for brand spanking new treatments.

Source:

University of California – San Diego

Journal reference:

Cobo, I., et al. (2022) DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages. Immunity. doi.org/10.1016/j.immuni.2022.06.022.