Mitochondria May Have Been Wrongly Accused in DNA Damage

Reactive oxygen species cause mutations to DNA bases that can lead to cancer, but the long-blamed mitochondria could have been wrongfully charged.

Shelby Bradford, PhD
| 4 min read
3D Illustration of a DNA molecule breaking apart into red pieces.

Reactive oxygen species can damage DNA. Scientists have assumed the main source of these was from mitochondria.

©istock, Dr_Microbe

Register for free to listen to this article
Listen with Speechify
0:00
4:00
Share

Normal metabolic activity produces reactive oxygen species (ROS) that, if not eliminated, can damage cellular components. As a result, ROS from overactive mitochondria are frequently cited as a source of DNA damage. Despite this longstanding belief, few studies have explicitly demonstrated this linkage.

Tobias Dansen, a redox biologist at the University Medical Center Utrecht, admits that even during his graduate studies, he believed that ROS produced by mitochondria could damage DNA. This idea began changing as he attended more meetings and met biochemists studying redox biology. “You start to realize that actually, to get from the mitochondria into the nucleus and damage the DNA, you have to pass a lot of stuff,” he said, adding that because of ROS’s reactivity, it would likely get caught along the way.

Two men stand side-by-side in a walk way for a photograph.
Tobias Dansen (left) and Daan van Soest (right) challenged the belief that mitochondrial ROS caused DNA damage, showing that these products don’t efficiently make it to the nucleus under normal conditions.
Veerle Hoeve

Dansen and his graduate student and study coauthor, Daan van Soest, put this assumption to the test. In a paper published in Nature Communications, the team demonstrated that hydrogen peroxide, a ROS produced by mitochondria, does not diffuse to the nucleus.1 Considering the presence of DNA bases mutated by hydroxy radicals in tumors, the findings support a nuclear source of ROS yet to be identified.

To specifically study the location-dependent effect of hydrogen peroxide release, they used D-amino acid oxidase (DAAO), which produces this ROS upon addition of D-alanine.2 The team fused DAAO to either a nucleosome protein or a mitochondrial membrane protein to study the effects of hydrogen peroxide produced at these specific locations.

Hydrogen peroxide poorly diffuses across the nuclear membrane, but the team evaluated if increased concentrations improved this migration. The fluorescent probe HyPer7 (a variant of an original probe, HyPer, named from hydrogen peroxide) activates in the presence of hydrogen peroxide.3,4 The group demonstrated that while hydrogen peroxide produced by DAAO in the nucleus activated nucleus-localized HyPer7, mitochondrial-bound DAAO did not significantly activate nuclear HyPer7 without toxic levels of hydrogen peroxide.

The team hypothesized that hydrogen peroxide levels below the detection of HyPer7 could still induce DNA damage. While nuclear DAAO activation kick-started DNA damage repair proteins and caused DNA strand breaks, mitochondrial-bound DAAO did not cause either of these effects. Additionally, DAAO-produced hydrogen peroxide at the mitochondria membrane did not induce cell cycle arrest, whereas hydrogen peroxide produced by DAAO in the nucleus paused the cell cycle.

While lower levels of hydrogen peroxide produced by DAAO at the mitochondrial membrane did not damage DNA or pause the cell cycle, higher concentrations reduced cells’ viability. The researchers confirmed that the increased production of hydrogen peroxide did not impede the function of mitochondria. They investigated a form of apoptosis caused by hydroxy radicals formed in the presence of iron and found that while these compounds contribute to cell death, cells still died in the presence of increased hydrogen peroxide, suggesting other mechanisms.

“It's going be interesting to see how quickly or readily this idea gets adopted that the [hydrogen peroxide] is not making it into the nucleus,” said Ryan Barnes, a cell biologist at the University of Kansas who was not involved in the study.

Fluorescent image showing high (orange/yellow) or low (purple/pink) levels of hydrogen peroxide in different cell locations.
A ROS produced by mitochondria does not efficiently migrate from the cytosol (left images) to the nucleus (right images), indicated by the color map.
Daan van Soest

Barnes, who found the study methodology rigorous, thought that the answer to the overarching question about mitochondrial ROS damaging DNA was convincing. However, he said that future experiments could explore how cancer evolution, which exposes cells to long-term hypoxic conditions, wears down antioxidant defenses and possibly alters the ability of hydrogen peroxide to diffuse to other locations.

According to Dansen, one thing that still puzzled him and his team was that they observed, like many others, that treating cells directly with hydrogen peroxide caused DNA damage responses and growth arrest, but the cells didn’t die. However, in their study, hydrogen peroxide produced at high levels at the mitochondria induced cell death before it could reach the nucleus. “That's something I cannot get my head around,” Dansen said. “It’s also one of the reasons this dogma was quite strong.” His group is currently investigating this discrepancy.

“It proves again that we have to be careful… to be aware of the dogmas that maybe are out there in biology,” van Soest said. “It just shows that we do have to constantly challenge also old ideas with the newer tools that are being developed over the years because…sometimes old ideas or old findings are not really explained well.”

Keywords

Meet the Author

  • Shelby Bradford, PhD

    Shelby Bradford, PhD

    Shelby is an assistant editor for The Scientist. She earned her PhD from West Virginia University in immunology and microbiology and completed an AAAS Mass Media fellowship.
Share
You might also be interested in...
Loading Next Article...
You might also be interested in...
Loading Next Article...
3D illustration of a gold lipid nanoparticle with pink nucleic acid inside of it. Purple and teal spikes stick out from the lipid bilayer representing polyethylene glycol.
February 2025, Issue 1

A Nanoparticle Delivery System for Gene Therapy

A reimagined lipid vehicle for nucleic acids could overcome the limitations of current vectors.

View this Issue
Considerations for Cell-Based Assays in Immuno-Oncology Research

Considerations for Cell-Based Assays in Immuno-Oncology Research

Lonza
An illustration of animal and tree silhouettes.

From Water Bears to Grizzly Bears: Unusual Animal Models

Taconic Biosciences
Sex Differences in Neurological Research

Sex Differences in Neurological Research

bit.bio logo
New Frontiers in Vaccine Development

New Frontiers in Vaccine Development

Sino

Products

Tecan Logo

Tecan introduces Veya: bringing digital, scalable automation to labs worldwide

Explore a Concise Guide to Optimizing Viral Transduction

A Visual Guide to Lentiviral Gene Delivery

Takara Bio
Inventia Life Science

Inventia Life Science Launches RASTRUM™ Allegro to Revolutionize High-Throughput 3D Cell Culture for Drug Discovery and Disease Research

An illustration of differently shaped viruses.

Detecting Novel Viruses Using a Comprehensive Enrichment Panel

Twist Bio