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MrPlow writes:

Submitted via IRC for SoyCow4408

Mitochondria are the "canary in the coal mine" for cellular stress:

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.

[...] 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 doxorubicin.

To destroy cancer, doxorubicin 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 doxorubicin when grown in culture dishes and even in mice, as higher levels of the ISGs were protecting the cell's DNA.

Journal Reference:
Zheng Wu, et al. Mitochondrial DNA stress signalling protects the nuclear genome. Nature Metabolism, 2019; 1 (12): 1209 DOI: 10.1038/s42255-019-0150-8

Original Submission