Mitochondria are the 'canary in the coal mine' for cellular stress

Illustration of mitochondria (stock image).

Credit: © RAJCREATIONZS / Adobe Stock

Mitochondria, tiny structures present in most cells, are known for their energy-generating machinery. Now, Salk researchers have discovered a new function of mitochondria: they set off molecular alarms when cells are exposed to stress or chemicals that can damage DNA, such as chemotherapy. The results, published online in Nature Metabolism on December 9, 2019, could lead to new cancer treatments that prevent tumors from becoming resistant to chemotherapy.

"Mitochondria are acting as a first line of defense in sensing DNA stress. The mitochondria tell the rest of the cell, 'Hey, I'm under attack, you better protect yourself,'" says Gerald Shadel, a professor in Salk's Molecular and Cell Biology Laboratory and the Audrey Geisel Chair in Biomedical Science.

Most of the DNA that a cell needs to function is found inside the cell's nucleus, packaged in chromosomes and inherited from both parents. But mitochondria each contain their own small circles of DNA (called mitochondrial DNA or mtDNA), passed only from a mother to her offspring. And most cells contain hundreds -- or even thousands -- of mitochondria.

Shadel's lab group previously showed that cells respond to improperly packaged mtDNA similarly to how they would react to an invading virus -- by releasing it from mitochondria and launching an immune response that beefs up the cell's defenses.

In the new study, Shadel and his colleagues set out to look in more detail at what molecular pathways are activated by the release of damaged mtDNA into the cell's interior. They homed in on a subset of genes known as interferon-stimulated genes, or ISGs, that are typically activated by the presence of viruses. But in this case, the team realized, the genes were a particular subset of ISGs turned on by viruses. And this same subset of ISGs is often found to be activated in cancer cells that have developed resistance to chemotherapy with DNA-damaging agents like doxyrubicin.

To destroy cancer, doxyrubicin targets the nuclear DNA. But the new study found that the drug also causes the damage and release of mtDNA, which in turn activates ISGs. This subset of ISGs, the group discovered, helps protect nuclear DNA from damage -- and, thus, causes increased resistance to the chemotherapy drug. When Shadel and his colleagues induced mitochondrial stress in melanoma cancer cells, the cells became more resistant to doxyrubicin when grown in culture dishes and even in mice, as higher levels of the ISGs were protecting the cell's DNA.

"Perhaps the fact that mitochondrial DNA is present in so many copies in each cell, and has fewer of its own DNA repair pathways, makes it a very effective sensor of DNA stress," says Shadel.

Most of the time, he points out, it's probably a good thing that the mtDNA is more prone to damage -- it acts like a canary in a coal mine to protect healthy cells. But in cancer cells, it means that doxyrubicin -- by damaging mtDNA first and setting off molecular alarm bells -- can be less effective at damaging the nuclear DNA of cancer cells.

"It says to me that if you can prevent damage to mitochondrial DNA or its release during cancer treatment, you might prevent this form of chemotherapy resistance," Shadel says.

His group is planning future studies on exactly how mtDNA is damaged and released and which DNA repair pathways are activated by the ISGs in the cell's nucleus to ward off damage.

Other authors on the study were Zheng Wu, Kailash Mangalhara, Alva Sainz, Laura Newman, Victoria Tripple and Susan Kaech of Salk; Sebastian Oeck, Lizhen Wu, Qin Yan, Marcus Bosenberg, Yanfeng Liu, Parker Sulkowski and Peter Glazer of Yale School of Medicine; Phillip West of Texas A&M College of Medicine; and Xiao-Ou Zhang of University of Massachusetts Medical School.

The work and the researchers involved were supported by grants from the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, the Office of the Assistant Secretary of Defense for Health Affairs, the China Scholarship Counsel, the Salk Excellerators Postdoctoral Fellowship, and the George E. Hewitt Foundation for Medical Research Postdoctoral Fellowship.

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Materials provided by Salk Institute. Note: Content may be edited for style and length.

Mitochondria are the 'canary in the coal mine' for cellular stress

Illustration of mitochondria

Mitochondria, tiny structures present in most cells, are known for their energy-generating machinery. Now, Salk researchers have discovered a new function of mitochondria: they set off molecular alarms when cells are exposed to stress or chemicals that can damage DNA, such as chemotherapy. The results, published online in Nature Metabolism on December 9, 2019, could lead to new cancer treatments that prevent tumors from becoming resistant to chemotherapy.

"Mitochondria are acting as a first line of defense in sensing DNA stress. The mitochondria tell the rest of the cell, 'Hey, I'm under attack, you better protect yourself,'" says Gerald Shadel, a professor in Salk's Molecular and Cell Biology Laboratory and the Audrey Geisel Chair in Biomedical Science.

Most of the DNA that a cell needs to function is found inside the cell's nucleus, packaged in chromosomes and inherited from both parents. But mitochondria each contain their own small circles of DNA (called mitochondrial DNA or mtDNA), passed only from a mother to her offspring. And most cells contain hundreds -- or even thousands -- of mitochondria.

Shadel's lab group previously showed that cells respond to improperly packaged mtDNA similarly to how they would react to an invading virus -- by releasing it from mitochondria and launching an immune response that beefs up the cell's defenses.

In the new study, Shadel and his colleagues set out to look in more detail at what molecular pathways are activated by the release of damaged mtDNA into the cell's interior. They homed in on a subset of genes known as interferon-stimulated genes, or ISGs, that are typically activated by the presence of viruses. But in this case, the team realized, the genes were a particular subset of ISGs turned on by viruses. And this same subset of ISGs is often found to be activated in cancer cells that have developed resistance to chemotherapy with DNA-damaging agents like doxyrubicin.

To destroy cancer, doxyrubicin targets the nuclear DNA. But the new study found that the drug also causes the damage and release of mtDNA, which in turn activates ISGs. This subset of ISGs, the group discovered, helps protect nuclear DNA from damage -- and, thus, causes increased resistance to the chemotherapy drug. When Shadel and his colleagues induced mitochondrial stress in melanoma cancer cells, the cells became more resistant to doxyrubicin when grown in culture dishes and even in mice, as higher levels of the ISGs were protecting the cell's DNA.

"Perhaps the fact that mitochondrial DNA is present in so many copies in each cell, and has fewer of its own DNA repair pathways, makes it a very effective sensor of DNA stress," says Shadel.

Most of the time, he points out, it's probably a good thing that the mtDNA is more prone to damage -- it acts like a canary in a coal mine to protect healthy cells. But in cancer cells, it means that doxyrubicin -- by damaging mtDNA first and setting off molecular alarm bells -- can be less effective at damaging the nuclear DNA of cancer cells.

"It says to me that if you can prevent damage to mitochondrial DNA or its release during cancer treatment, you might prevent this form of chemotherapy resistance," Shadel says.

His group is planning future studies on exactly how mtDNA is damaged and released and which DNA repair pathways are activated by the ISGs in the cell's nucleus to ward off damage.

Other authors on the study were Zheng Wu, Kailash Mangalhara, Alva Sainz, Laura Newman, Victoria Tripple and Susan Kaech of Salk; Sebastian Oeck, Lizhen Wu, Qin Yan, Marcus Bosenberg, Yanfeng Liu, Parker Sulkowski and Peter Glazer of Yale School of Medicine; Phillip West of Texas A&M College of Medicine; and Xiao-Ou Zhang of University of Massachusetts Medical School.

The work and the researchers involved were supported by grants from the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, the Office of the Assistant Secretary of Defense for Health Affairs, the China Scholarship Counsel, the Salk Excellerators Postdoctoral Fellowship, and the George E. Hewitt Foundation for Medical Research Postdoctoral Fellowship.

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Materials provided by Salk Institute. Note: Content may be edited for style and length.

Measuring methane from coal and gas in Pennsylvania informative

Measuring methane from coal and gas

While methane pollution caused by natural gas production in Pennsylvania is underestimated by the U.S. Environmental Protection Agency, natural gas still has half the carbon footprint of underground coal mining, according to an international team of researchers.

"At the rates we found for methane, natural gas in Pennsylvania is still much, much cleaner than coal," said Zachary Barkley research associate in meteorology, Penn State. "Obviously, renewable energy would be better, but there is no debate, switching to natural gas is worth it in the short run."

The researchers looked at methane in the atmosphere by flying transects over the southwestern portion of Pennsylvania and adjacent portions of West Virginia and Ohio. Researchers from the University of Maryland collected data from the flights.

"The southwestern part of the state has huge amounts of natural gas and coal and we were getting methane from there during a previous project in northeastern Pennsylvania," said Barkley.

The southwestern area of Pennsylvania has long been a coal mining area and drilling into the Marcellus shale also has increased the numbers of unconventional natural gas wells in the area. The EPA estimates the amounts of methane put into the atmosphere from both coal mining and natural gas drilling every year.

Because both sources of methane exist in the same area, the researchers could not just measure methane and separate the sources. To determine the split between coal and natural gas, the researchers looked at the amounts of both methane and ethane and determined that more ethane is produced from natural gas wells, than from coal mines. They reported their results in a recent issue of Geophysical Research Letters.

Using the ratio of methane to ethane, the researchers found that the amount of methane released to the atmosphere from coal mines was very close to the EPA estimates, but that the amounts of methane from unconventional natural gas wells were between two to eight times the estimated EPA amounts. The EPA estimate is about 0.1 percent leakage, while the study found about 0.5 percent leakage. However, they note that because the wells in the Marcellus shale are such high-production wells, the net impact on climate of this natural gas production is still much lower than from coal mines after accounting for emissions from energy generation.

"High-producing wells have a much lower leakage rate than older wells which only produce 2 to 3 percent of Pennsylvania gas, but are estimated to produce about 40 percent of the state's total emission of methane from natural gas," said Barkley.

The researchers suggest that using the ratio of methane to ethane in other areas where emissions are from mixed sources could help to tease out the percentages of the carbon footprint from each source.

"Burning fossil fuel, whether coal or gas, is bad for the climate," said Kenneth J. Davis, professor of atmospheric and climate science, Penn State. "These underground coal mines are clearly more damaging than Marcellus gas production, but the gas production isn't as clean as we thought. We need more data like this to inform energy policy."

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Materials provided by Penn State. Note: Content may be edited for style and length.