Mitochondrial misfire sparks inflammation

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Cells in the human body contain energy-producing mitochondria, each with its own mtDNA-; A unique set of genetic instructions completely separate from the cell’s nuclear DNA that mitochondria use to generate life-giving energy. When mtDNA is where it belongs (inside the mitochondria), it maintains both mitochondrial and cellular health-; But when it goes where no This can trigger an immune response that promotes inflammation.

Now, Salk scientists and collaborators at UC San Diego have discovered a novel mechanism used to remove defective mtDNA from inside mitochondria to the outside. When this happens, mtDNA is flagged as foreign DNA and activates a cellular pathway that is normally used to promote inflammation to eliminate pathogens such as viruses.

Results, published Nature Cell Biology On February 8, 2024, we offer several new targets for therapeutics to disrupt inflammatory pathways and therefore reduce inflammation during aging and disease, such as lupus or rheumatoid arthritis.

We knew that mtDNA was escaping from the mitochondria, but how was still clear. Using imaging and cell biology approaches, we were able to trace the steps in the pathway to remove mtDNA from mitochondria, which we can now try to target with therapeutic interventions to hopefully prevent the resulting inflammation.”


Professor Gerald Schedel, senior and co-corresponding author, is director of the San Diego-Nathan Schock Center of Excellence in the Basic Biology of Aging and holder of the Audrey Geisel Chair in Biomedical Sciences at Salke.

One way our cells respond to damage and infection is known as the innate immune system. Although the innate immune response is the first line of defense against viruses, it can also respond to molecules in the body that simply resemble pathogens—including misplaced mtDNA. This response can lead to chronic inflammation and contribute to human disease and aging.

Scientists are working to unravel how mtDNA leaves the mitochondria and triggers the innate immune response, but previously developed pathways did not apply to the unique mtDNA stress conditions that the Salk team was investigating. So, they turned to sophisticated imaging techniques to gather clues about where and when things are going awry in those mitochondria.

“We had a huge breakthrough when we saw that mtDNA was inside a mysterious membrane structure when it left the mitochondria-; after putting all the puzzle pieces together, we realized that the structure was an endosome,” said first author Laura Newman, a former postdoctoral researcher. in Shadel’s lab and is currently an assistant professor at the University of Virginia. “Ultimately this discovery led us to the realization that the mtDNA is unfolding and, in the process, some of it is coming out.”

The team discovered a process that begins with an error in mtDNA replication that causes mtDNA-containing protein masses to pile up inside mitochondria called nucleoids. Noticing this error, the cell then begins to remove the replication-stopping nucleosides by transporting them to endosomes, a collection of organelles that sort and send cellular material for permanent disposal. Endosomes become overloaded with these nucleoids, a leak occurs, and mtDNA is suddenly released into the cell. The cell flags the mtDNA as foreign DNA—the same way it flags virus DNA—and initiates the DNA-sensing cGAS-sting pathway to trigger inflammation.

“Using our state-of-the-art imaging tools to investigate mitochondrial dynamics and mtDNA release, we have discovered a completely novel release mechanism for mtDNA,” said co-corresponding author Uri Manor, former director of Salk’s WET Advanced Biophotonics Core and current assistant professor. at UC San Diego. “There are many follow-up questions we can’t wait to ask, such as how other interactions between organelles regulate innate immunity, how different cell types express mtDNA, and how we can target this new pathway to reduce inflammation during disease and aging. I can.”

The researchers hope to further map this complex mtDNA-disposal and immune-activation pathway, including any biological context-; such as mtDNA replication dysfunction and viral infections; What is needed to initiate the pathway and what downstream effects it may have on human health. . They also see an opportunity for therapeutic innovation using this pathway, which presents a new cellular target to reduce inflammation.

Other authors include Sammy Weiser Novak, Gladys Rojas, Nimesha Tadepalle, Cara Schiavone, Christina Towers, Matthew Donnelly, Sagnika Ghosh, Sienna Rocha, and Salk’s Ricardo Rodriguez-Enriquez; Daniel Grotzan and Michaela Medina of The Scripps Research Institute; Marie-Yve Tremblay of the University of Victoria, Canada; Joshua Chavez of UC San Diego; and Ian Lemersal of the La Jolla Institute for Immunology.

This work was supported by the National Institutes of Health (R01 AR069876, P30AG068635, 1K99GM141482, 1F32GM137580, T32GM007198, 5R00CA245187, and 5R00CA245187, and 5R00CA245187, and 5R00CA245187). was Cognitive Impairment Award (19PA). BH134610000H), a National Science Foundation Neuronex Award (2014862), Chan-Zuckerberg Initiative Imaging Scientist Award, Life Foundation, George E. Hewitt Foundation for Medical Research Postdoctoral Fellowship, Paul F. Glenn Foundation for Medical Research Postdoctoral Fellowship, Salk Pioneer Fund Postdoctoral Scholar Award, Waite Foundation, Yale University School of Medicine Center for Cellular and Molecular Imaging, a Canada Research Chair (Tier 2) Neurobiology of Aging and Cognitionand a Canada Foundation for Innovation John R. Evans Leaders Fund (Grant 39965).

Source:

Journal Reference:

Newman, L. E., etc. (2024). Mitochondrial DNA replication stress triggers the pro-inflammatory endosomal pathway of nucleoid disposal. Nature Cell Biology. doi.org/10.1038/s41556-023-01343-1.



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