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Developmental Biology - Mitochondria
How Some Cancers Resist Chemotherapy
Mitochondria are 'canaries in the coal mine' for cell stress...
Mitochondria are tiny structures present in most cells and are known as 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 - such as chemotherapy - that can damage DNA.
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 — Alert, under attack, protect yourself."
Gerald Shadel PhD, Professor the Audrey Geisel Chair in Biomedical Science, Salk Molecular and Cell Biology Laboratory, La Jolla, California, USA.
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 each mitochondria contains small circles of DNA (called mitochondrial DNA or mtDNA), passed only from a mother to her offspring. Most cells also 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 that mtDNA and launching an immune response to beef up that 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, which are typically activated by the presence of virus. But in this case, the team realized these genes were a particular subset of ISGs responding to virus.
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 nuclear DNA. But this new study finds the drug also causes damage and release of mtDNA, which in turn activates ISGs. This subset of ISGs, the group discovered, helps protect nuclear DNA from damage — thus causing increased resistance to chemotherapy drugs.
When Shadel and his colleagues induced mitochondrial stress in melanoma cancer cells grown in culture dishes, the cells became more resistant to doxyrubicin, 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."
Gerald S. Shadel PhD.
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."
Gerald S. Shadel PhD
Shadel's group is planning future studies on exactly how mtDNA is damaged and released — and which DNA repair pathways are activated to ward off damage by ISGs in the cell's nucleus.
Abstract
The mammalian genome comprises nuclear DNA (nDNA) derived from both parents and mitochondrial DNA (mtDNA) that is maternally inherited and encodes essential proteins required for oxidative phosphorylation. Thousands of copies of the circular mtDNA are present in most cell types that are packaged by TFAM into higher-order structures called nucleoids1. Mitochondria are also platforms for antiviral signalling2 and, due to their bacterial origin, mtDNA and other mitochondrial components trigger innate immune responses and inflammatory pathology2,3. We showed previously that cytoplasmic release of mtDNA activates the cGAS–STING–TBK1 pathway resulting in interferon-stimulated gene (ISG) expression that promotes antiviral immunity4. Here, we find that persistent mtDNA stress is not associated with basally activated NF-?B signalling or interferon gene expression typical of an acute antiviral response. Instead, a specific subset of ISGs that includes Parp9 remains activated by the unphosphorylated form of ISGF3 that enhances nDNA damage and repair responses. In cultured primary fibroblasts and cancer cells, the chemotherapeutic drug doxorubicin causes mtDNA damage and release, which leads to cGAS–STING–dependent ISG activation. In addition, mtDNA stress in TFAM-deficient mouse melanoma cells produces tumours that are more resistant to doxorubicin in vivo. Finally, Tfam+/- mice exposed to ionizing radiation exhibit enhanced nDNA repair responses in spleen. Therefore, we propose that damage to and subsequent release of mtDNA elicits a protective signalling response that enhances nDNA repair in cells and tissues, suggesting that mtDNA is a genotoxic stress sentinel.
Authors
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; and Gerald Shadel, Salk Institute.
Acknowledgments
The authors thank A. Iwasaki and C. Dela-Cruz for reagents and advice, A. Mennone Jr. and T. Zhang for assistance with microscopy, C. O’Connor for help with cell sorting and flow cytometry, M. Leblanc and Y.-L. Chang for mouse tissue collection, S. O. Kelley and T. Sack for providing mitochondria-targeted doxorubicin, and N. Varki and the UCSD histopathology core for preparation and analysis of mouse tissues. This work was supported by NIH grant no. R01 AR069876 and the Audrey Geisel Chair in Biomedical Science to G.S.S., NIH grant no. R01 CA216101 to G.S.S and S.M.K., NIH grant no. R35 CA197574 to P.M.G., NIH grant no. R01 CA237586 to Q.Y., NIH grant no. F31 AG062099 to A.G.S. and NIH grant no. P50 CA121974. A.P.W. was supported by grant no. RP170734 from the Cancer Prevention and Research Institute of Texas and grant no. W81XWH-17-1-0052 from the Office of the Assistant Secretary of Defense for Health Affairs, Peer Reviewed Medical Research Program. Z.W. was supported by the China Scholarship Counsel, K.C.M. by the Salk Excellerators Postdoctoral Fellowship and L.E.N. by the George E. Hewitt Foundation for Medical Research Postdoctoral Fellowship.
About the Salk Institute for Biological Studies: Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.
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Dec 23 2019 Fetal Timeline Maternal Timeline News
 cell nuclei (blue) mtDNA (white) SALK.png) Pictured are mitochondria (red), mtDNA (white dots) and cell nuclei (blue). CREDIT Salk Institute-Waitt Advanced Biophotonics Center.
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