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Scientists find surprising link between mitochondrial DNA and increased atherosclerosis risk

Scientists find surprising link between mitochondrial DNA and increased atherosclerosis risk
Human blood cells following reduced expression of the gene DNMT3A. The cell nuclei (large green structures) in the cytoplasmic protein (red). Some mitochondrial DNA (small green dots) has escaped in to the cytoplasm, inducing an inflammatory response. Credit: Isidoro Cobo of UC NORTH PARK

Mitochondria are referred to as cells’ powerhouses, but mounting evidence suggests in addition they are likely involved in inflammation. Scientists from the Salk Institute and UC NORTH PARK published new findings in Immunity on July 26, 2022, where they examined human blood cells and discovered a surprising link between mitochondria, inflammation and DNMT3A and TET2two genes that normally help regulate blood cell growth but, when mutated, are connected with an increased threat of atherosclerosis.

“We discovered that the genes DNMT3A and TET2, along with their normal job of altering chemical tags to modify DNA, directly activate expression of a gene involved with mitochondrial inflammatory pathways, which hints at a fresh molecular target for atherosclerosis therapeutics,” says Gerald Shadel, co-senior author, Salk professor and director of the NORTH PARK Nathan Shock Center of Excellence in the essential Biology of Aging.

The analysis started when researchers at UC NORTH PARK noted a particular inflammatory response while investigating the roles of DNMT3A and TET2 mutations in clonal hematopoiesiswhen mutated immature bring about a population of mature blood with identical mutations. They reported that abnormal inflammatory signaling was also linked to DNMT3A and TET2 deficiency in blood that play a significant role in response that promotes the progression of atherosclerosis.

But the way the DNMT3A and TET2 genes were involved with inflammation, and perhaps atherosclerosis, was unknown.

“The issue was we couldn’t workout how DNMT3A and TET2 were involved as the proteins they code do seemingly opposite things regarding DNA regulation,” says Christopher Glass, co-senior author and professor at the UC NORTH PARK School of Medicine. “Their antagonistic activity led us to trust there could be other mechanisms at play. This prompted us to have a different approach and contact Shadel, who had uncovered exactly the same inflammatory pathway years earlier while examining responses to mitochondrial DNA stress.”

Inside mitochondria resides a distinctive subset of the cell’s DNA that must definitely be organized and condensed correctly to sustain normal function. Shadel’s team previously investigated the consequences of mitochondrial DNA stress by detatching TFAM, a gene that helps to ensure mitochondrial DNA is packaged correctly. They discovered that when TFAM levels are reduced, mitochondrial DNA is expelled from the mitochondria in to the cell’s interior. This cause exactly the same molecular alarm that tells the cell there exists a bacterial or viral invader and triggers a defensive molecular pathway that promotes inflammation.

Scientists from the Glass and Shadel labs worked together to raised realize why DNMT3A and TET2 mutations resulted in inflammation responses much like those observed during mitochondrial DNA stress. The teams applied genetic engineering tools and cell imaging to look at cells from people who have normal cells, people that have lack of function mutations in DNMT3A or TET2 expression, and the ones with atherosclerosis.

They discovered that experimentally reducing the expression of DNMT3A or TET2 in the standard blood cells had similar leads to blood cells that had lack of function mutations and from atherosclerosis patientsan increased inflammatory response. Remarkably, low degrees of DNMT3A and TET2 expression in blood results in reduced TFAM expression, which results in abnormal mitochondria DNA packaging, instigating inflammation because of released mitochondrial DNA.

“We found that DNMT3A and TET2 mutations prevent their capability to bind and activate the TFAM gene,” says first author Isidoro Cobo, a postdoctoral researcher in the Glass lab at UC NORTH PARK. “Missing or reducing this binding activity results in mitochondrial DNA release and an overactive mitochondrial inflammation response, and we believe this might exacerbate plaque buildup in atherosclerosis.”

“It is rather exciting to see our discovery on TFAM depletion causing mitochondrial DNA stress and inflammation now has direct relevance for an illness like atherosclerosis,” says Shadel, who holds the Audrey Geisel Chair in Biomedical Science. “Since we revealed this pathway, there’s been an explosion of fascination with mitochondria being involved with inflammation and several reports linking mitochondrial DNA release to other clinical contexts.”

Therapeutics that target signaling pathways already exist for most other diseases. Glass and Shadel think that blocking pathways that exacerbate atherosclerosis in patients with TET2A and DNMT3A mutations can form the foundation for new treatments. Next, the scientists will continue investigating this pathway and probe how mitochondrial DNA is involved with other human diseases and aging.

Other authors included Kailash Chandra Mangalhara of Salk; Tiffany N. Tanaka, Addison Lana, Calvin Yeang, Claudia Han, Johannes Schlachetzki, Jean Challcombe, Bethany R. Fixsen, Mashito Sakai, Rick Z. Li, Hannah Fields, Randy G. Tsai and Rafael Bejar of UC NORTH PARK; Michael Mokry of Wilhelmina Children’s hospital in holland; Koen Prange and Menno de Winther of the University of Amsterdam.

More info: DNMT3A and TET2 restrain mitochondrial DNA-mediated interferon signaling in macrophages, Immunity (2022). DOI: 10.1016/j.immuni.2022.06.022

Citation: Scientists find surprising link between mitochondrial DNA and increased atherosclerosis risk (2022, August 21) retrieved 21 August 2022 from

This document is at the mercy of copyright. Aside from any fair dealing for the intended purpose of private study or research, no part could be reproduced minus the written permission. This content is provided for information purposes only.

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