Mitochondria are organelles found within most cells, best known for generating the chemical energy required to power cellular functions. Increasingly, however, researchers are discovering how mitochondrial function -; and dysfunction -; play critical roles in numerous diseases, and even aging.
In a new study published in 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 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 as a new molecular target for atherosclerosis therapeutics. They also interact with mitochondrial inflammatory pathways, which hints at a new molecular target for atherosclerosis therapeutics."
Gerald Shadel, PhD, co-senior study author and director of the San Diego Nathan Shock Center of Excellence in 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 new blood cells with the same genetic mutation, co-senior study 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 inflammation response that promotes development of atherosclerosis.
But the question remained how DNMT3A and TET2 genes were involved in inflammation and atherosclerosis -; the buildup of fatty plaques in arteries and the primary underlying cause of cardiovascular disease. It is estimated approximately half of Americans between the ages of 45 and 84 have atherosclerosis, which is the single leading cause of death in the United States and westernized nations.
"The problem was we couldn't work out how DNMT3A and TET2 were involved because the proteins they code seemingly do opposite things regarding DNA regulation," said Glass. "Their antagonistic activity led us to believe there may be other mechanisms at play, which 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."
Inside mitochondria resides a unique subset of the cell's DNA that must be organized and condensed correctly to sustain normal function. Shadel's team had previously investigated the effects of mitochondrial DNA stress by removing TFAM, a gene that helps ensure mitochondrial DNA is packaged correctly.
Shadel and colleagues determined that when TFAM levels are reduced, mitochondrial DNA is expelled from mitochondria into the cell's interior, setting off the same 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 better understand why DNMT3A and TET2 mutations led to inflammatory responses similar to those observed during mitochondrial DNA stress. The teams applied genetic engineering tools and cell imaging to examine cells from people with normal cells, those with loss of function mutations in DNMT3A or TET2 expression and those with atherosclerosis.
They discovered that experimentally reducing the expression of DNMT3A or TET2 in normal blood cells produced similar results to blood cells that had loss of function mutations and to blood cells from atherosclerosis patients. 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 TFAM expression, which in turn led to abnormal mitochondria DNA packaging, instigating inflammation due to released mitochondrial DNA.
"We discovered that DNMT3A and TET2 mutations prevent their ability to bind and activate the TFAM gene," said first author Isidoro Cobo, PhD, a postdoctoral scholar in Glass' lab. "Missing or reducing this binding activity leads to mitochondrial DNA release and an overactive mitochondrial inflammation response. We believe this may exacerbate plaque buildup in atherosclerosis."
Shadel said the findings broaden and deepen understanding of mitochondrial function and their role in disease.
"It's very 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 has been an explosion of interest in mitochondria being involved in inflammation and many reports linking mitochondrial DNA release to other clinical contexts."
Therapeutics that target inflammation signaling pathways already exist for many 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.
Source:
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.
Read this article:
Mitochondrial DNA mutations are associated with an increased risk of atherosclerosis - News-Medical.Net
- Distinguished investigator brings expertise in genetics and cell biology to Texas A&M AgriLife - AgriLife Today - October 26th, 2024 [October 26th, 2024]
- Institute of Molecular and Cell Biology (IMCB) - Agency for Science, Technology and Research (A*STAR) - October 13th, 2024 [October 13th, 2024]
- Joseph Gall, father of modern cell biology, dead at 96 - Carnegie Institution for Science - September 15th, 2024 [September 15th, 2024]
- A dual role of ERGIC-localized Rabs in TMED10-mediated unconventional protein secretion - Nature.com - June 27th, 2024 [June 27th, 2024]
- Yoshihiro Yoneda Appointed President of the International Human Frontier Science Program Organization - PR Newswire - June 27th, 2024 [June 27th, 2024]
- A new way to measure ageing and disease risk with the protein aggregation clock - EurekAlert - June 18th, 2024 [June 18th, 2024]
- How Flow Cytometry Spurred Cell Biology - The Scientist - June 18th, 2024 [June 18th, 2024]
- Building Cells from the Bottom Up - The Scientist - June 18th, 2024 [June 18th, 2024]
- From Code to Creature - The Scientist - June 18th, 2024 [June 18th, 2024]
- Adding intrinsically disordered proteins to biological ageing clocks - Nature.com - May 24th, 2024 [May 24th, 2024]
- Advancing Cell Biology and Cancer Research via Cell Culture and Microscopy Imaging Techniques - Lab Manager Magazine - May 24th, 2024 [May 24th, 2024]
- Study explores how different modes of cell division evolved in close relatives of fungi and animals - News-Medical.Net - May 24th, 2024 [May 24th, 2024]
- Solving the Wnt nuclear puzzle - Nature.com - May 24th, 2024 [May 24th, 2024]
- Prof. Jay Shendure Joins Somite Therapeutics as Scientific Co-founder - BioSpace - May 24th, 2024 [May 24th, 2024]
- One essential step for a germ cell, one giant leap for the future of reproductive medicine - EurekAlert - May 24th, 2024 [May 24th, 2024]
- May: academy-medical-sciences | News and features - University of Bristol - May 24th, 2024 [May 24th, 2024]
- Universal tool for tracking cell-to-cell interactions - ASBMB Today - May 24th, 2024 [May 24th, 2024]
- Close Encounters of Skin and Nerve Cells - The Scientist - April 15th, 2024 [April 15th, 2024]
- OrthoID: Decoding Cellular Conversations with Cutting-Edge Technology - yTech - April 15th, 2024 [April 15th, 2024]
- Impact of aldehydes on DNA damage and aging - EurekAlert - April 15th, 2024 [April 15th, 2024]
- Redefining Cell Biology: Nondestructive Genetic Insights With Raman Spectroscopy - SciTechDaily - March 29th, 2024 [March 29th, 2024]
- Scientists Unravel the Unusual Cell Biology Behind Toxic Algal Blooms - SciTechDaily - March 19th, 2024 [March 19th, 2024]
- Ancient retroviruses played a key role in the evolution of vertebrate brains - EurekAlert - February 21st, 2024 [February 21st, 2024]
- Singapore scientists uncover a crucial link between cholesterol synthesis and cancer progression - EurekAlert - February 4th, 2024 [February 4th, 2024]
- Scientists uncover a way to "hack" neurons' internal clocks to speed up brain cell development - News-Medical.Net - February 4th, 2024 [February 4th, 2024]
- First atomic-scale 'movie' of microtubules under construction, a key process for cell division - EurekAlert - February 4th, 2024 [February 4th, 2024]
- Small RNAs take on the big task of helping skin wounds heal better and faster with minimal scarring - EurekAlert - February 4th, 2024 [February 4th, 2024]
- Shengjie Feng channels the powers of cryogenic electron microscopy - Newswise - January 19th, 2024 [January 19th, 2024]
- Study pinpoints breast cancer cells-of-origi - EurekAlert - January 19th, 2024 [January 19th, 2024]
- New analysis of cancer cells identifies 370 targets for smarter, personalized treatments - News-Medical.Net - January 19th, 2024 [January 19th, 2024]
- EU funding for pioneering research on the treatment of gliomas - EurekAlert - January 19th, 2024 [January 19th, 2024]
- The future of mRNA biology and AI convergence - Drug Target Review - December 22nd, 2023 [December 22nd, 2023]
- The future of artificial breast milk, according to one lab - Quartz - December 22nd, 2023 [December 22nd, 2023]
- Shedding new light on the hidden organization of the cytoplasm - News-Medical.Net - December 22nd, 2023 [December 22nd, 2023]
- Bugs that help bugs: How environmental microbes boost fruit fly reproduction - EurekAlert - December 22nd, 2023 [December 22nd, 2023]
- Cells Move in Groups Differently Than They Do When Alone - NYU Langone Health - December 14th, 2023 [December 14th, 2023]
- Cells move in groups differently than they do when alone - EurekAlert - December 14th, 2023 [December 14th, 2023]
- Seattle Hub for Synthetic Biology plans to transform cells into tiny recording devices - GeekWire - December 14th, 2023 [December 14th, 2023]
- Virginia Tech and Weizmann Institute of Science tackle cell ... - Virginia Tech - October 16th, 2023 [October 16th, 2023]
- Vast diversity of human brain cell types revealed in trove of new ... - Spectrum - Autism Research News - October 16th, 2023 [October 16th, 2023]
- Singamaneni to develop advanced protein imaging method - The ... - Washington University in St. Louis - October 16th, 2023 [October 16th, 2023]
- Researchers find certain cancers can activate 'enhancer' in the ... - University of Toronto - October 16th, 2023 [October 16th, 2023]
- 2023 Hettleman Prizes awarded to five exceptional early-career ... - UNC Research - October 16th, 2023 [October 16th, 2023]
- Faeth Therapeutics Announces National Academy of Medicine ... - BioSpace - October 16th, 2023 [October 16th, 2023]
- From Migrant Farm Worker to Duke Scientist, Everardo Macias ... - Duke University School of Medicine - October 16th, 2023 [October 16th, 2023]
- Finding the golden ticket? Cyclin T1 is required for HIV-1 latency ... - Fred Hutch News Service - October 16th, 2023 [October 16th, 2023]
- Spermidine May Improve Egg Health and Fertility - Lifespan.io News - October 16th, 2023 [October 16th, 2023]
- Molecule discovered that grows bigger and stronger muscles - Earth.com - October 16th, 2023 [October 16th, 2023]
- SGIOY: 3 Biotech Stocks With Potential Future Gains - StockNews.com - October 16th, 2023 [October 16th, 2023]
- Association for Molecular Pathology Publishes Best Practice ... - Technology Networks - October 16th, 2023 [October 16th, 2023]
- A new cell type with links to gastric cancer steps up for its mugshot - Fred Hutch News Service - October 16th, 2023 [October 16th, 2023]
- Programmed cell death may be 1.8 billion year - EurekAlert - October 16th, 2023 [October 16th, 2023]
- New study confirms presence of flesh-eating and illness-causing ... - Science Daily - October 16th, 2023 [October 16th, 2023]
- New Institute for Immunologic Intervention (3i) at the Hackensack ... - Hackensack Meridian Health - October 16th, 2023 [October 16th, 2023]
- Post-doctoral Fellow in Cancer Biology in the Department of ... - Times Higher Education - October 16th, 2023 [October 16th, 2023]
- Scientists uncover key enzymes involved in bacterial pathogenicity - News-Medical.Net - October 16th, 2023 [October 16th, 2023]
- B cell response after influenza vaccine in young and older adults - EurekAlert - October 16th, 2023 [October 16th, 2023]
- Post-doctoral researcher in yeast cell biology job with UNIVERSITY ... - Times Higher Education - April 8th, 2023 [April 8th, 2023]
- expert reaction to study looking at creating embryo-like structures ... - Science Media Centre - April 8th, 2023 [April 8th, 2023]
- UCF Bone Researcher Receives National Recognition - UCF - April 8th, 2023 [April 8th, 2023]
- PhenomeX to Participate in American Association of Cancer ... - BioSpace - April 8th, 2023 [April 8th, 2023]
- Inland Empire stem-cell therapy gets $2.9 million booster - UC Riverside - April 8th, 2023 [April 8th, 2023]
- New finding in roundworms upends classical thinking about animal cell differentiation - News-Medical.Net - April 8th, 2023 [April 8th, 2023]
- Biology's unsolved chicken-or-egg problem: Where did life come from? - Big Think - April 8th, 2023 [April 8th, 2023]
- Azacitidine in Combination With Trametinib May Be Effective for ... - The ASCO Post - April 8th, 2023 [April 8th, 2023]
- Researchers clear the way for well-rounded view of cellular defects - Phys.org - April 8th, 2023 [April 8th, 2023]
- We were dancing around the lab cellular identity discovery has potential to impact cancer treatments - Newswise - April 8th, 2023 [April 8th, 2023]
- Environmental stressors' effect on gene expression explored in lecture - Environmental Factor Newsletter - April 8th, 2023 [April 8th, 2023]
- RNA therapy restores gene function in monkeys modeling ... - Spectrum - Autism Research News - April 8th, 2023 [April 8th, 2023]
- Traumatic brain injury interferes with immune system cells' recycling ... - Science Daily - April 8th, 2023 [April 8th, 2023]
- Lab-grown fat could give cultured meat real flavor and texture - EurekAlert - April 8th, 2023 [April 8th, 2023]
- Researchers reveal mechanism of polarized cortex assembly in migrating cells - Phys.org - April 8th, 2023 [April 8th, 2023]
- Probing Selfish Centromeres Unveils an Evolutionary Arms Race - The Scientist - April 8th, 2023 [April 8th, 2023]
- Meet the 2023 Outstanding Graduating Students - UMaine News ... - University of Maine - April 8th, 2023 [April 8th, 2023]
- The Worlds Sexiest Fragrance Unveiled, But Its Not For You - Revyuh - April 8th, 2023 [April 8th, 2023]
- City of Hope appoints John D. Carpten, Ph.D., as director of its ... - BioSpace - April 8th, 2023 [April 8th, 2023]
- Modernized Algorithm Predicts Drug Targets for SARS-CoV-2, Other ... - GenomeWeb - April 8th, 2023 [April 8th, 2023]
- BU researcher wins $3.9 million NIH grant to develop novel therapeutic modalities for Alzheimer's - News-Medical.Net - April 8th, 2023 [April 8th, 2023]
- Providing critical insights for animal development - HKU biologists ... - EurekAlert - April 8th, 2023 [April 8th, 2023]
- Students Express Frustrations About the Middle Class Scholarship - The Triton - April 8th, 2023 [April 8th, 2023]