Hutch News

Separate rulebook for cellular powerhouses

A precise new technique reveals that our cells’ engines, mitochondria, unexpectedly shrug off DNA damage from toxic chemicals

Sept. 1, 2016
Dr. Jason Bielas

Dr. Jason Bielas, a researcher in Fred Hutch's Public Health Sciences and Human Biology divisions.

Photo by Robert Hood / Fred Hutch News Service

Mitochondria, our tiny cellular powerhouses, play by their own rules when it comes to withstanding DNA damage, according to newly published findings.

Mitochondria produce the energy our cells need to run, and to do it they rely on their own set of genes, separate from those housed in our nuclei, the cells’ control centers.  But surprisingly, instead of falling prey to DNA damage that would cause rampant genetic errors in the DNA of a cell’s nucleus, mitochondria are able to somehow outrun this damage and keep their DNA error-free, scientists at Fred Hutchinson Cancer Research Center have shown.

“Everyone thinks DNA damage and mutation always go hand in hand, but it’s simply not true,” said Fred Hutch senior author Dr. Jason Bielas, who studies how errors in the genetic code of mitochondrial and nuclear DNA contribute to disease. His findings were published Aug. 22 in the journal Nucleic Acids Research.

Bielas and his team at Fred Hutch had previously developed a technique that allows them to precisely and accurately measure — for the first time — genetic errors, or mutations, in mitochondrial DNA. With collaborators at University of Washington and Health Canada, Bielas and first author William Valente, a graduate student in Bielas’ lab, used this method to examine how two DNA-damaging chemicals influence the mutation rate in mitochondrial DNA — only to discover that they didn’t.

An unexpected finding

Our cells contain 100 to 1,000 mitochondria to generate the energy our cells need. Most of our genes are encoded in DNA contained in the nucleus, which acts a bit like the cell’s decision-making center, but each mitochondrion carries its own copy of the mitochondrial genome — a set of genes unique from those within the nuclear genome. 

Mutations in mitochondrial genes are thought to contribute to everything from aging to cancer. The mutation rate in the mitochondria is much higher — about 100 times higher — than the mutation rate in the nucleus. It was thought that this substantial difference was due to a higher vulnerability to DNA damage in mitochondria.

Bielas saw in mitochondria a golden opportunity. A higher mutation rate equals more mitochondrial mutations which, in theory, would be easier to detect than rare mutations in the nucleus. Exposure to certain environmental chemicals, like those found in coal tar, can lead to cancer-causing mutations, but it’s difficult to accurately assess each individual’s level of exposure. Mitochondria, Bielas thought, could serve as easily read sensors of toxic exposure.

“It made sense to use mitochondria [as a biomarker to monitor environmental exposures] because it has been theorized that mitochondria would be more sensitive to increased mutations than the nucleus, giving us a bigger window to look into the role environmental toxins play in cancer development,” he said. But Bielas was stymied by the fact that whatever chemical he threw on cultured human or mouse cells, he could never detect the expected increase in mutation in their mitochondria.

“This research has been going on for nine years, but we never published anything because we always questioned the results,” said Bielas, who initially exposed cells to mutagens in dishes in the lab. Worrying, among other things, that their detection methods were too crude, his group developed two highly sensitive techniques that can detect single point mutations and sections of deleted DNA with great accuracy.

He and his team decided they needed to address this disconnect between the lab results and common assumptions regarding DNA damage in mitochondria.

William Valente

William Valente, a graduate student in lab of Dr. Jason Bielas.

Photo by Robert Hood / Fred Hutch News Service

Damaged DNA? No problem

Valente and Bielas collaborated with scientists at Health Canada who are experts in screening compounds for their ability to cause genetic mutations. They chose to test the effects of benzo[a]pyrene (B[a]P), a combustion byproduct found in tobacco smoke and coal tar, and N-ethyl-N-nitrosourea (ENU), known as a “super mutagen” for its incredible ability to induce mutations in nuclear DNA.

The group exposed mice to three different doses of B[a]P or one dose of ENU — daily — for four weeks. Then, they examined mitochondria from bone marrow and liver for an uptick in genetic errors.

After four weeks, no dose of either B[a]P or ENU had caused an increase in the rate of deletions or changes in specific bases in mitochondrial DNA extracted from either liver or bone marrow. In contrast, the frequency of mutations in nuclear DNA skyrocketed — increasing anywhere from four to over 150 times the usual rate, depending on mutagen, dose and tissue source.

Bielas and Valente feared that somehow, the B[a]P and ENU were not reaching mitochondrial DNA, so they took a step back and examined DNA damage instead — usually a precursor to mutations. After even a single dose of B[a]P, the scientists found copious amounts of damage to mitochondrial DNA, suggesting that somehow, mitochondria can prevent DNA damage from resulting in mistakes in the genetic code.

“We still don’t know what’s going on,” Bielas said. “But it seems that mitochondria have mechanisms to repress this kind of induced mutation, which nobody has really figured out.”

A new mitochondrial mystery to solve

The findings — that DNA-damaging chemicals fail to induce mutations in mitochondria even when they cause expected DNA damage — upend conventional wisdom, and raise many new questions. How do mitochondria keep from accumulating mutations from environmental damage when they are missing some of the better-known strategies that nuclei use to clean up damaged DNA? What is causing their higher rate of mutation? If it is due to damage from the reactive molecules that mitochondria produce during their usual energy-generating process, why are they susceptible to that particular type of DNA mutation?

The study also raises the possibility that it’s not mutations in mitochondria but the damaged DNA itself that contributes to aging and cancer, Bielas said. The results also show that mitochondria are not the hoped-for canaries in the coal mines of exposure to environmental chemicals that Bielas was seeking.

“We don’t usually publish negative results, but it’s an important result,” he said. Other scientists are also pinning their hopes on mitochondria as measures of environmental exposures. Now, said Bielas, “it’s important for them to move on, and concentrate their efforts elsewhere.”

In science, when one door closes, another always opens. How, exactly, mitochondria sidestep the usual result of DNA damage remains a mystery. To discover how mitochondria sidestep that typical outcome, Bielas and his team must throw out what they’ve learned from the nucleus and write a new rulebook.

“We’re definitely looking at [the mechanism], but I think this finding will get more researchers looking into what’s going on,” Bielas said.

 

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Sabrina Richards is a staff writer at Fred Hutchinson Cancer Research Center. She has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.

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