Mitochondria, tiny structures that are found in most cells, are known for their power generation machinery. Now Salk researchers have discovered a new function of mitochondria: They trigger molecular alarms when cells are exposed to stress or chemicals that can damage the DNA, e.g. B. Chemotherapy. The results, published online in Nature Metabolism on December 9, 2019, could lead to new cancer therapies that prevent tumors from becoming resistant to chemotherapy.
"Mitochondria are the first line of defense in detecting DNA stress. Mitochondria tell the rest of the cell," Hey, I'm under attack, you better protect yourself, "said Gerald Shadel, professor of Salks Molecular and Laboratory for Cell Biology and Audrey -Geisel Chair in Biomedicine.
Most of the DNA that a cell needs to function is located in the nucleus, packaged in chromosomes and inherited from both parents. But mitochondria each contain their own small circles of DNA (mitochondrial DNA or mtDNA) that only a mother passes on to her offspring. And most cells contain hundreds or even thousands of mitochondria.
Shadel's group had previously shown that cells respond to improperly packaged mtDNA, much like they would respond to an invading virus - by releasing it from the mitochondria and triggering an immune response that strengthens the cell's defenses.
In the new study, Shadel and his colleagues wanted to investigate more closely which molecular pathways are activated by the release of damaged mtDNA into the cell interior. They looked at a subset of genes known as interferon-stimulated genes or ISGs, which are typically activated by the presence of viruses. In this case, however, the team found that the genes were a specific subset of ISGs that were activated by viruses. The same subset of ISGs are often activated in cancer cells that have developed resistance to chemotherapy with DNA-damaging agents such as doxyrubicin.
To destroy cancer, doxyrubicin targets the core DNA. However, the new study found that the drug also causes the damage and release of mtDNA, which in turn activates ISGs. This subset of ISGs, according to the group, protects 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 in culture dishes and even in mice became more resistant to doxyrubicin because higher ISG levels protected the cell's DNA.
"Perhaps the fact that mitochondrial DNA is present in so many copies in every cell and has fewer DNA repair pathways of its own makes it a very effective sensor for DNA stress," says Shadel.
Most of the time, he emphasizes, it's probably a good thing that mtDNA is more susceptible to damage - it acts like a canary in a coal mine to protect healthy cells. In cancer cells, however, this means that doxyrubicin - by first damaging the mtDNA and triggering molecular alarm bells - is less effective in damaging the nuclear DNA of cancer cells.
"If you don't damage mitochondrial DNA or its release during cancer treatment, you can prevent this form of chemotherapy resistance," says Shadel.
His group plans future studies on how exactly mtDNA is damaged and released and which DNA repair pathways are activated by the ISGs in the cell nucleus to ward off damage.
Other authors of the study were Zheng Wu, Kailash Mangalhara, Alva Sainz, Laura Newman, Victoria Tripple and Susan Kaech von Salk; Sebastian Oeck, Lizhen Wu, Qin Yan, Marcus Bosenberg, Yanfeng Liu, Parker Sulkowski and Peter Glazer from the Yale School of Medicine; Phillip West from A&M College of Medicine, Texas; and Xiao-Ou Zhang from the University of Massachusetts Medical School.
The work and researchers involved were supported by grants from the National Institutes of Health, the Cancer Prevention and Research Institute in Texas, the Office of the Secretary of Defense for Health, the China Scholarship Counsel, the Salk Excellerators Postdoctoral Fellowship, and the University of Texas E. Hewitt Foundation for Medical Research Postdoctoral Fellowship.
Zheng Wu, Sebastian Oeck, A. Phillip West, Kailash C. Mangalhara, Alva G. Sainz, Laura E. Newman, Xiao-Ou Zhang, Lizhen Wu, Qin Yan, Marcus Bosenberg, Yanfeng Liu, Parker L. Sulkowski, Victoria Tripple, Susan M. Kaech, Peter M. Glazer, Gerald S. Shadel. Mitochondrial DNA stress signalling protects the nuclear genome. Nature Metabolism, 2019; 1 (12): 1209 DOI: 10.1038/s42255-019-0150-8